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Cited by 591Adipose Tissue and MetabolismRegulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic Diseases

Cellular bioenergetics as a target for obesity therapy

Open access
Tseng, Yu-Hua, Cypess, Aaron M., Kahn, C. Ronald·2010·Nature Reviews Drug Discovery
DOI 10.1038/nrd3138PMC PMC2880836
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Abstract

Obesity develops when energy intake exceeds energy expenditure. Although most current obesity therapies are focused on reducing calorific intake, recent data suggest that increasing cellular energy expenditure (bioenergetics) may be an attractive alternative approach. This is especially true for adaptive thermogenesis — the physiological process whereby energy is dissipated in mitochondria of brown fat and skeletal muscle in the form of heat in response to external stimuli. There have been significant recent advances in identifying the factors that control the development and function of these tissues, and in techniques to measure brown fat in human adults. In this article, we integrate these developments in relation to the classical understandings of cellular bioenergetics to explore the potential for developing novel anti-obesity therapies that target cellular energy expenditure.

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Written from the paper’s full text.

TL;DR

This review argues that increasing cellular energy expenditure through adaptive thermogenesis—especially in brown adipose tissue (BAT) and skeletal muscle—is an attractive alternative strategy for obesity therapy. It integrates bioenergetics, the rediscovery of functional BAT in adult humans, developmental regulators of brown fat, and candidate therapeutic approaches, while emphasizing unresolved safety and efficacy questions.

Key findings

  • Obesity develops when energy intake exceeds energy expenditure; current FDA-approved weight-loss drugs mainly reduce intake, but targeting energy expenditure may help overcome homeostatic reductions in BMR and defend against weight regain.
  • Adult humans possess functional UCP1-positive BAT, identified by PET/CT; prevalence estimates vary from <10% in retrospective case series to 96% among younger people after cold stimulation, and BAT activity correlates inversely with BMI and percentage body fat.
  • Human BAT may be quantitatively important: as little as 50 g of BAT (<0.1% of body weight) could utilize up to 20% of basal caloric needs if maximally stimulated, and BAT is estimated to be 100–200 times more effective as a thermogenic organ per gram than muscle.
  • Potential therapeutic approaches include increasing brown fat differentiation (e.g., BMP-7, FGFs), activating BAT (e.g., β3 agonists, thyroid mimetics, TGR5 agonist INT-777), promoting skeletal muscle thermogenesis (e.g., resveratrol, AICAR, GW1516), and increasing general mitochondrial uncoupling (e.g., DNP, which at 3–5 mg/kg increased energy expenditure by 20–30% but is unsafe).

Methods

  • Narrative review; no primary data, systematic search strategy, or formal meta-analysis is described.
  • Synthesizes classic cellular bioenergetics, rodent and human studies, PET/CT imaging findings, developmental biology of brown fat, and pharmacological approaches.
  • Main analysis is qualitative integration of literature to identify therapeutic targets and remaining questions.

Limitations

  • The paper states that many questions remain: whether chronic increases in peripheral energy expenditure cause compensatory appetite increases; the exact contributions of BAT and skeletal muscle to human adaptive thermogenesis, especially after overfeeding; and the cellular lineage and developmental fate factors for energy-dissipating brown fat.
  • The paper states high safety concerns for anti-obesity treatments and notes unresolved BAT thermogenesis safety questions, including whether stimulated BAT could induce necrosis, raise body temperature dangerously, or increase cardiac demand enough to contraindicate treatment in the elderly or those with heart disease.
  • Evident from the text: this is a narrative review rather than a systematic review, and PET/CT limitations are noted—CT cannot yet distinguish brown from white fat, and factors such as dietary fatty acids and beta-adrenergic blockers can alter 18F-FDG uptake.

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Integrity signals

Registry

Crossref · 10.1038/nrd3138

Cites

208 of 208 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 243 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Myf5-negative progenitors isolated from adult mouse skeletal muscle can differentiate into brown fat in vitro.

    “Likewise, we have found that myf5-negative progenitors isolated from adult mouse skeletal muscle can differentiate into brown fat in vitro (Tseng et al., manuscript submitted).”
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    • cites Tseng et al., manuscript submitted

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  • Premiseown data

    Almost all of the over two-dozen treatments in at least Phase 1 clinical trials are aimed at reducing energy intake.

    “There are over two-dozen treatments in at least Phase 1 clinical trials, and more in the pipeline (Table 1A, Table 1B, and Table 2), almost all of which are aimed at reducing energy intake.”
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    • cites Table 1A

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    • cites Table 1B

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    • cites Table 2

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  • Premisecitation

    Only a small portion of individuals on dietary and/or exercise programs maintain a long-term weight loss.

    “Unfortunately, only a small portion of individuals on dietary and/or exercise programs maintain a long-term weight loss 4.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Wing, R. R. & Phelan, S. Long-term weight loss maintenance. Am. J. Clin. Nutr. 82, 222S–225S (2005). source

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  • Premisecitation

    Adaptive thermogenesis occurs primarily in the mitochondria of skeletal muscle and brown fat.

    “These latter forms of regulated heat production are referred to as adaptive thermogenesis 3, and occur primarily in the mitochondria of skeletal muscle and brown fat, which are distinct from other body tissues in that their thermogenesis is finely regulated and therefore has the potential to be manipulated therapeutically to serve as a target for obesity treatment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Lowell, B. B. & Spiegelman, B. M. Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652–660 (2000). source

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  • Premisecitation

    Triglyceride/fatty acid cycling is involved in the thermogenesis associated with burn injuries, cancer cachexia, and after exercise.

    “This cycling is involved in the thermogenesis associated with burn injuries 26, cancer cachexia 27, and after exercise 28.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [26] Wolfe, R. R., Herndon, D. N., Jahoor, F., Miyoshi, H. & Wolfe, M. Effect of severe burn injury on substrate cycling by glucose and fatty acids. N. Engl. J. Med. 317, 403–408 (1987). source

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    • cites [27] Klein, S. & Wolfe, R. R. Whole-body lipolysis and triglyceride-fatty acid cycling in cachectic patients with esophageal cancer. J. Clin. Invest. 86, 1403–1408 (1990). source

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    • cites [28] Wolfe, R. R., Klein, S., Carraro, F. & Weber, J. M. Role of triglyceride–fatty acid cycle in controlling fat metabolism in humans during and after exercise. Am. J. Physiol. 258, E382–E389 (1990).

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    Premisecitation

    These medications have thus far met limited success because of unacceptable side effects or inadequate long-term clinical efficacy.

    “However, because of the unacceptable side effects or inadequate long-term clinical efficacy, these medications have thus far met limited success 7.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Melnikova, I. & Wages, D. Anti-obesity therapies. Nature Rev. Drug Discov. 5, 369–370 (2006). source

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  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Increasing cellular energy expenditure may be an attractive alternative approach for obesity therapy.

    “While most current obesity therapies are focused on reducing caloric intake, recent data suggest that increasing cellular energy expenditure (bioenergetics) may be an attractive alternative approach.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Obesity develops when energy intake exceeds energy expenditure.

  • May combine two claims.

    Premisecitation

    The only three drugs currently approved by the FDA specifically for weight loss decrease energy intake, either by acting at satiety centers in the brain (sibutramine and phentermine) or by reducing the efficiency of intestinal absorption (orlistat).

    “The only three drugs currently approved by the FDA specifically for weight loss decrease energy intake, either by acting at satiety centers in the brain (sibutramine and phentermine) or by reducing the efficiency of intestinal absorption (orlistat) 5, thereby reducing the elevated energy intake that is critical in maintaining the obese state 6.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Kaplan, L. M. Pharmacological therapies for obesity. Gastroenterol. Clin. North Am. 34, 91–104 (2005). source

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  • May combine two claims.

    Interpretationreasoning

    The thermogenesis of skeletal muscle and brown fat is finely regulated and has the potential to be manipulated therapeutically as a target for obesity treatment.

    “These latter forms of regulated heat production are referred to as adaptive thermogenesis 3, and occur primarily in the mitochondria of skeletal muscle and brown fat, which are distinct from other body tissues in that their thermogenesis is finely regulated and therefore has the potential to be manipulated therapeutically to serve as a target for obesity treatment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Lowell, B. B. & Spiegelman, B. M. Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652–660 (2000). source

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  • May combine two claims.

    Premisecitation

    Muscle tissue has at least four uncoupled, or energy-burning, reactions, including (1) the energy dissipated as heat by the inwardly rectifying Ca2+ and Na+ channels; (2) cycling of actinomyosin during contraction and relaxation; (3) heat dissipated during physical work and (4) energy lost by triglyceride/fatty acid cycling.

    “Muscle tissue has at least four uncoupled, or energy-burning, reactions, including (1) the energy dissipated as heat by the inwardly rectifying Ca2+ and Na+ channels; (2) cycling of actinomyosin during contraction and relaxation; (3) heat dissipated during physical work and (4) energy lost by triglyceride/fatty acid cycling (Figures 2b–2d) 2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Rolfe, D. F. & Brown, G. C. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol. Rev. 77, 731–758 (1997). source

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    Premisecitation

    The integrated systems by which the brain and body communicate to regulate body weight may indicate single or multiple set-points for weight that may be difficult to adjust.

    “The integrated systems by which the brain and body communicate to regulate body weight may indicate single or multiple set-points for weight that may be difficult to adjust 12,19–21.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [12] Leibel, R. L., Rosenbaum, M. & Hirsch, J. Changes in energy expenditure resulting from altered body weight. N. Engl. J. Med. 332, 621–628 (1995). This paper demonstrates that changes in body weight by diet are associated with compensatory changes in energy expenditure, which may account for the poor long-term efficacy of treatments for obesity. source

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    • cites [19] Gosselin, C. & Cote, G. Weight loss maintenance in women two to eleven years after participating in a commercial program: a survey. BMC Womens Health 1, 2 (2001). source

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    • cites [20] Tam, J., Fukumura, D. & Jain, R. K. A mathematical model of murine metabolic regulation by leptin: energy balance and defense of a stable body weight. Cell. Metab. 9, 52–63 (2009). source

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    • cites [21] Chow, C. C. & Hall, K. D. The dynamics of human body weight change. PLoS Comput. Biol. 4, e1000045 (2008). source

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    Premisecitation

    Dinitrophenol (DNP), a non-selective uncoupler of mitochondrial oxidation, effectively increases energy expenditure that could be sustained without tolerance.

    “For example, dinitrophenol (DNP), a non-selective uncoupler of mitochondrial oxidation, effectively increases energy expenditure that could be sustained without tolerance 18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Harper, M. E., Green, K. & Brand, M. D. The efficiency of cellular energy transduction and its implications for obesity. Annu. Rev. Nutr. 28, 13–33 (2008). This comprehensive review discusses bioenergetics and the reasons for targeting uncoupling for the treatment of obesity. source

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    Premisecitation

    UCP1 is unique to BAT and is necessary to mediate BAT thermogenesis.

    “UCP1 is unique to BAT and is necessary to mediate BAT thermogenesis 30.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Golozoubova, V. et al. Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. FASEB J. 15, 2048–2050 (2001). source

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    Premisecitation

    Under normal circumstances, in most tissues, the release of energy in chemical bonds is mediated enzymatically as a series of interconnected reactions that permit the minimization of loss as heat and maximization of production of ATP.

    “Under normal circumstances, in most tissues, the release of the energy in chemical bonds is mediated enzymatically 22 as a series of interconnected reactions that permit the minimization of loss as heat and maximization of production of ATP.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Green, D. E. & Zande, H. D. Universal energy principle of biological systems and the unity of bioenergetics. Proc. Natl Acad. Sci. USA 78, 5344–5347 (1981). source

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    Premisecitation

    Recent studies have shown that adult humans maintain potentially active brown adipose tissue, making this high energetic tissue a real therapeutic target.

    “Second, recent studies have shown that adult humans maintain potentially active brown adipose tissue, making this high energetic tissue a real therapeutic target 13–17.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [13] Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009). source

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    • cites [14] Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009). source

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    • cites [15] Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009). source

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    • cites [16] Saito, M. et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58, 1526–1531 (2009). source

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    • cites [17] Zingaretti, M. C. et al. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J. 23, 3113–3120 (2009). References 13–17 report the rediscovery of metabolically active brown fat in adult humans using non-invasive PET and CT scans coupled with immunohistochemistry, electron microscopy, and gene and protein expression assays. These led to the consideration that brown fat may play a role in normal physiology and could be a target for obesity treatment. source

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  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Drug treatment targeting energy expenditure might only need to be short-term or intermittent, reducing the risks and costs of lifelong exposure to medications.

    “This raises the possibility that drug treatment might only need to be short-term or intermittent, reducing the risks and costs of lifelong exposure to medications.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Redundant systems are in place to overcome any one pathway to appetite suppression, suggesting that a drug acting by one principal mechanism may be unlikely to have long-term efficacy.

    “Therefore, redundant systems are in place to overcome any one pathway to appetite suppression, suggesting that a drug acting by one principal mechanism may be unlikely to have long-term efficacy.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Wells, J. C. Thrift: a guide to thrifty genes, thrifty phenotypes and thrifty norms. Int. J. Obes. (Lond.) 33, 1331–1318 (2009). source

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    • cites [9] Speakman, J. R. A nonadaptive scenario explaining the genetic predisposition to obesity: the “predation release” hypothesis. Cell. Metab. 6, 5–12 (2007). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Bioenergetics takes place largely within the mitochondria, where, through the TCA cycle and ETC, energy from nutrients is released; oxygen is consumed; and water, carbon dioxide, and ATP are produced.

    “Bioenergetics takes place largely within the mitochondria, where, through the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC), energy from nutrients is released; oxygen is consumed; and water, carbon dioxide, and ATP are produced (Box 1, Figure 2a).”
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    • cites Box 1

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    • cites Figure 2a

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  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Premisecitation

    Differential responses to DIT may account for the large individual differences in weight gain in response to overfeeding and thus contribute to the development of obesity.

    “It has been proposed that differential responses to DIT may account for the large individual differences in weight gain in response to overfeeding and thus contribute to the development of obesity 49.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Rothwell, N. J. & Stock, M. J. A role for brown adipose tissue in diet-induced thermogenesis. Nature 281, 31–35 (1979). This paper establishes the importance of diet-induced thermogenesis via the function of brown fat in energy balance, and suggests that BAT plays a key part in metabolic efficiency and resistance to obesity. source

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  • May combine two claims.

    Premisenone given

    Cold exposure induces shivering thermogenesis (ST), a function of skeletal muscle, and non-shivering thermogenesis (NST), a function of brown fat.

    “Cold exposure induces shivering thermogenesis (ST), a function of skeletal muscle, and non-shivering thermogenesis (NST), a function of brown fat.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Figure 1

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    Premisenone given

    Overfeeding triggers diet-induced thermogenesis (DIT), a function of brown fat.

    “Overfeeding triggers diet-induced thermogenesis (DIT); this is also a function of brown fat.”
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    • cites Figure 1

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    Premisecitation

    Newborn human infants cannot shiver, and thus maintenance of body temperature depends entirely on NST by brown fat.

    “Newborn human infants cannot shiver, and thus maintenance of body temperature depends entirely on NST by brown fat 47.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Lean, M. E., James, W. P., Jennings, G. & Trayhurn, P. Brown adipose tissue uncoupling protein content in human infants, children and adults. Clin. Sci. (Lond.) 71, 291–297 (1986). source

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    Premisecitation

    Humans have much greater body mass (~200X), only moderately greater BAT mass (~10X), and much lower basal metabolic rate (~0.15X) than rats.

    “Humans are quite different from rats, with much greater body mass (~200X), only moderately greater BAT mass (~10X), and much lower basal metabolic rate (~0.15X) 13,37,36.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009). source

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    • cites [37] Mifflin, M. D. et al. A new predictive equation for resting energy expenditure in healthy individuals. Am. J. Clin. Nutr. 51, 241–247 (1990). source

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    • cites [36] Foster, D. O. & Frydman, M. L. Tissue distribution of cold-induced thermogenesis in conscious warm- or cold-acclimated rats reevaluated from changes in tissue blood flow: the dominant role of brown adipose tissue in the replacement of shivering by nonshivering thermogenesis. Can. J. Physiol. Pharmacol. 57, 257–270 (1979). source

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  • May combine two claims.

    Premisecitation

    Ablation of BAT leads to reduced energy expenditure and increased obesity on high fat diet.

    “Conversely, ablation of BAT leads to reduced energy expenditure and increased obesity on high fat diet 75.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Lowell, B. B. et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366, 740–742 (1993). This study uses a transgenic toxigene approach to ablate BAT in mice, and demonstrates that brown fat deficiency leads to increased metabolic efficiency and obesity. source

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  • May combine two claims.

    Premisecitation

    Glucocorticoids do not directly increase thermogenesis, but they may have an important role in coordinating the thermogenic response to substrate and food availability.

    “Glucocorticoids similarly do not directly increase thermogenesis, but they may have an important role in coordinating the thermogenic response to substrate and food availability 65.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Silva, J. E. Thermogenic mechanisms and their hormonal regulation. Physiol. Rev. 86, 435–464 (2006). source

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    Premisecitation

    In response to cold exposure or overfeeding, norepinephrine released from the SNS regulates brown adipocytes at multiple levels: it promotes proliferation and differentiation of brown preadipocytes, directly regulates the thermogenic program of BAT by activation of UCP1 gene, and protects brown adipocytes from TNFα-induced apoptosis.

    “In response to cold exposure or overfeeding, norepinephrine released from the SNS regulates brown adipocytes at multiple levels: it promotes proliferation and differentiation of brown preadipocytes, directly regulates the thermogenic program of BAT by activation of UCP1 gene, and protects brown adipocytes from TNFα-induced apoptosis 63.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004). source

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    Interpretationcitation

    The identification of functional brown adipose tissue in adult humans has led to a rethinking that BAT may play a role in normal physiology and could be a target for obesity treatment.

    “This identification of functional brown adipose tissue in adult humans has led to a rethinking within the medical and scientific communities that BAT may play a role in normal physiology and could be a target for obesity treatment 81,85.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] Nedergaard, J., Bengtsson, T. & Cannon, B. Unexpected evidence for active brown adipose tissue in adult humans. Am. J. Physiol. Endocrinol. Metab. 293, E444–E452 (2007). source

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    • cites [85] Ravussin, E. & Kozak, L. P. Have we entered the brown adipose tissue renaissance? Obes. Rev. 10, 265–268 (2009). source

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  • May combine two claims.

    Premisecitation

    UCP1-ablated mice are more susceptible to cold and have to rely on shivering for thermoregulation.

    “Thus, UCP1-ablated mice are more susceptible to cold and have to rely on shivering for thermoregulation 31.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Enerback, S. et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 90–94 (1997). source

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  • May combine two claims.

    Premisecitation

    Leptin, released by white adipocytes, regulates energy balance by effects on the hypothalamus that lead to inhibition of food intake and increased thermogenesis via activation of the SNS.

    “In addition, leptin, released by white adipocytes, regulates energy balance by effects on the hypothalamus that lead to inhibition of food intake and increased thermogenesis via activation of the SNS, though to date there is limited evidence that leptin mediates thermogenesis via the SNS in humans 66–70.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [66] Mistry, A. M., Swick, A. G. & Romsos, D. R. Leptin rapidly lowers food intake and elevates metabolic rates in lean and ob/ob mice. J. Nutr. 127, 2065–2072 (1997). source

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    • cites [67] Commins, S. P. et al. Norepinephrine is required for leptin effects on gene expression in brown and white adipose tissue. Endocrinology 140, 4772–4778 (1999). source

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    • cites [68] Elmquist, J. K., Maratos-Flier, E., Saper, C. B. & Flier, J. S. Unraveling the central nervous system pathways underlying responses to leptin. Nature Neurosci. 1, 445–449 (1998). source

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    • cites [69] Harris, R. B. Leptin — much more than a satiety signal. Annu. Rev. Nutr. 20, 45–75 (2000). source

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    • cites [70] Rosenbaum, M. et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J. Clin. Invest. 115, 3579–3586 (2005). source

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    Premisecitation

    Attempts to find functional BAT or utilize its thermogenesis for weight loss in humans have been largely unsuccessful.

    “Histological evidence has indicated that brown fat is present, albeit in small amounts, in adults, throughout life 76, but attempts to find functional BAT 77 or utilize its thermogenesis for weight loss 78,79 have been largely unsuccessful.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [77] Astrup, A. Thermogenesis in human brown adipose tissue and skeletal muscle induced by sympathomimetic stimulation. Acta Endocrinol. Suppl. (Copenh.) 278, 1–32 (1986).

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    • cites [78] Weyer, C., Tataranni, P. A., Snitker, S., Danforth, E. Jr & Ravussin, E. Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective β3-adrenoceptor agonist in humans. Diabetes 47, 1555–1561 (1998). source

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    • cites [79] Larsen, T. M. et al. Effect of a 28-d treatment with L-796568, a novel β3-adrenergic receptor agonist, on energy expenditure and body composition in obese men. Am. J. Clin. Nutr. 76, 780–788 (2002). source

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    Premisecitation

    Insulin can affect thermogenesis by increasing substrate uptake by BAT and increasing hypothalamic-mediated sympathetic activity.

    “Insulin can affect thermogenesis by increasing substrate uptake by BAT and increasing hypothalamic-mediated sympathetic activity 71, both of which may be connected to the thermic effect of food 72.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Ferrannini, E. et al. Insulin: new roles for an ancient hormone. Eur. J. Clin. Invest. 29, 842–852 (1999). source

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    Premisecitation

    Induction of BAT in mice promotes energy expenditure, reduces adiposity, and protects mice from diet-induced obesity.

    “Induction of BAT in mice promotes energy expenditure, reduces adiposity, and protects mice from diet-induced obesity 73,74.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [73] Ghorbani, M., Claus, T. H. & Himms-Hagen, J. Hypertrophy of brown adipocytes in brown and white adipose tissues and reversal of diet-induced obesity in rats treated with a β3-adrenoceptor agonist. Biochem. Pharmacol. 54, 121–131 (1997). source

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    • cites [74] Guerra, C., Koza, R. A., Yamashita, H., Walsh, K. & Kozak, L. P. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J. Clin. Invest. 102, 412–420 (1998). This paper reports that genetic backgrounds affect the emergence of brown adipocytes within white fat in response to β 3 -adrenergic receptor stimulation. source

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    Premisecitation

    When kept at thermoneutrality, UCP1 knockout mice lack DIT and develop obesity, indicating that diet-induced thermogenesis is fully dependent on UCP1.

    “When kept at thermoneutrality (30 °C for mice), UCP1 knockout mice lack DIT and develop obesity 33, indicating that diet-induced thermogenesis is fully dependent on UCP1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Feldmann, H. M., Golozoubova, V., Cannon, B. & Nedergaard, J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell. Metab. 9, 203–209 (2009). This paper demonstrates that diet-induced thermogenesis is fully dependent on UCP1, thus Ucp1 -knockout mice exhibit increased susceptibility to diet-induced obesity when kept at thermoneutrality. source

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    Premisecitation

    Adipose tissue is generally considered to arise from multipotent mesenchymal stem cells of mesodermal origin.

    “Adipose tissue is generally considered to arise from the multipotent mesenchymal stem cells of mesodermal origin 89.”
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    • cites [89] Gesta, S., Tseng, Y. H. & Kahn, C. R. Developmental origin of fat: tracking obesity to its source. Cell 131, 242–256 (2007). source

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  • May combine two claims.

    Premisecitation

    Functional BAT decreases with age, and is rarely observed in non-stimulated overweight adults over 64 years-old, suggesting a possible role of decreased BAT activity in the development of age-related obesity.

    “Functional BAT also decreases with age, and is rarely observed in non-stimulated [i.e. no investigator-controlled stimulation such as cold or pharmacological interventions], overweight adults over 64 years-old 13, suggesting a possible role of decreased BAT activity in the development of age-related obesity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BAT activity correlates inversely with BMI and percentage body fat, suggesting a role in energy balance.

    “More importantly, BAT activity correlates inversely with BMI13,14 and percentage body fat 13,14, suggesting a role in energy balance.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009). source

      Not checked in the free run.

    • cites [14] Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vivo fate mapping has shown that progenitors derived from the central dermomyotome give rise to the interscapular brown fat cells, suggesting that the interscapular brown fat and skeletal muscle may share a common developmental ancestry.

    “In vivo fate mapping has shown that progenitors derived from the central dermomyotome give rise to the interscapular brown fat cells 90, suggesting that the interscapular brown fat and skeletal muscle may share a common developmental ancestry.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Atit, R. et al. β-Catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev. Biol. 296, 164–176 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Drugs which can increase BAT activity may be useful in combating obesity, and in older adults, may help restore a component of normal human physiology.

    “Together, these findings suggest that drugs which can increase BAT activity may be useful in combating obesity, and in older adults, may help restore a component of normal human physiology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PET/CT positivity shows seasonal variation, indicating a role of BAT in normal adaptation to cold.

    “PET/CT positivity shows seasonal variation 13,16,88, indicating a role of BAT in normal adaptation to cold.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009). source

      Not checked in the free run.

    • cites [16] Saito, M. et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58, 1526–1531 (2009). source

      Not checked in the free run.

    • cites [88] Cohade, C., Mourtzikos, K. A. & Wahl, R. L. “USA-Fat”: prevalence is related to ambient outdoor temperature-evaluation with 18F-FDG PET/CT. J. Nucl. Med. 44, 1267–1270 (2003).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Not all brown fat cells are derived from myf5-expressing progenitors; brown fat cells emerging in white fat in response to β3-adrenergic stimulation are not marked by the myf5-driven fluorescent protein.

    “However, not all brown fat cells are derived from myf5-expressing progenitors. For example, the brown fat cells emerging in white fat in response to β3-adrenergic stimulation are not marked by the myf5-driven fluorescent protein 92.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008). References 90–92 demonstrate a common developmental ancestry for interscapular brown fat and skeletal muscle in mice. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The inverse correlation between BAT activity and obesity was seen despite the fact that lean and overweight subjects had similar resting metabolic rates in both thermoneutral and cold exposure, suggesting that overweight people increase their energy expenditure using different physiological mechanisms.

    “This inverse correlation between BAT activity and obesity was seen despite the fact that the lean and overweight subjects had similar resting metabolic rates in both thermoneutral and cold exposure, suggesting that overweight people increase their energy expenditure using different physiological mechanisms 14.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BMP-2 and 4 promote white fat differentiation, while BMP-7 serves as a potent inductive signal for brown adipogenesis.

    “While BMP-2 and 4 promote white fat differentiation, BMP-7 serves as a potent inductive signal for brown adipogenesis 101.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Tseng, Y. H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008). This paper identifies BMP7 as an inducer of brown adipocyte differentiation, and demonstrates that adenoviral-mediated expression of BMP7 in mice leads to increased brown fat-mediated energy expenditure and reduced weight gain. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice that overexpress FGF-21, a circulating FGF which is induced by a ketogenic diet, are lean and have increased brown fat, suggesting that the beneficial metabolic effects induced by a ketogenic diet are brought about in part by increases in BAT mass.

    “Interestingly, mice that overexpress FGF-21, a circulating FGF which is induced by a ketogenic diet 106, are lean and have increased brown fat 107, suggesting that the beneficial metabolic effects induced by a ketogenic diet are brought about in part by increases in BAT mass.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [106] Badman, M. K. et al. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell. Metab. 5, 426–437 (2007). source

      Not checked in the free run.

    • cites [107] Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115, 1627–1635 (2005). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    FGF-16 mRNA is expressed predominantly in brown adipose tissue during embryonic days 17.5-19.5, and thereafter at lower levels into the neonatal period.

    “FGF-16 mRNA is expressed predominantly in brown adipose tissue during embryonic days 17.5–19.5, and thereafter at lower levels into the neonatal period 104.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Konishi, M., Mikami, T., Yamasaki, M., Miyake, A. & Itoh, N. Fibroblast growth factor-16 is a growth factor for embryonic brown adipocytes. J. Biol. Chem. 275, 12119–12122 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BMPs are a family of developmental regulators belonging to the TGF-β superfamily, which promote adipogenesis at different stages.

    “BMPs are a family of developmental regulators belonging to the TGF-β superfamily, which promote adipogenesis at different stages 100.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Schulz, T. J. & Tseng, Y. H. Emerging role of bone morphogenetic proteins in adipogenesis and energy metabolism. Cytokine. Growth Factor Rev. 20, 523–531 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Systemic brown adipocytes are often found admixed with white fat cells; are more sensitive to β3-adrenergic stimulation and cold exposure; and their thermogenic capacity appears to be regulated by genetic background.

    “These systemic brown adipocytes are often found admixed with white fat cells; are more sensitive to β3-adrenergic stimulation and cold exposure; and their thermogenic capacity appears to be regulated by genetic background 86,87,74.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [86] Almind, K., Manieri, M., Sivitz, W. I., Cinti, S. & Kahn, C. R. Ectopic brown adipose tissue in muscle provides a mechanism for differences in risk of metabolic syndrome in mice. Proc. Natl Acad. Sci. USA 104, 2366–2371 (2007). source

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    • cites [87] Xue, B. et al. Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat. J. Lipid Res. 48, 41–51 (2007). source

      Not checked in the free run.

    • cites [74] Guerra, C., Koza, R. A., Yamashita, H., Walsh, K. & Kozak, L. P. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J. Clin. Invest. 102, 412–420 (1998). This paper reports that genetic backgrounds affect the emergence of brown adipocytes within white fat in response to β 3 -adrenergic receptor stimulation. source

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  • May combine two claims.

    Premisecitation

    BMP-7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate - PRDM16 and PGC-1α, increased expression of adipogenic transcription factors - PPARγ and C/EBPs, mitochondrial biogenesis, and increased expression of UCP1.

    “BMP-7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate - PRDM16 and PGC-1α, increased expression of adipogenic transcription factors - peroxisome proliferator-activated receptor (PPAR)γ and CCAAT/enhancer-binding proteins (C/EBPs), mitochondrial biogenesis, and increased expression of UCP1 (Figure 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Tseng, Y. H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008). This paper identifies BMP7 as an inducer of brown adipocyte differentiation, and demonstrates that adenoviral-mediated expression of BMP7 in mice leads to increased brown fat-mediated energy expenditure and reduced weight gain. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both insulin and IGF-1 protect brown precursor cells from apoptosis, and this effect is mainly mediated by IRS-1.

    “Both insulin and IGF-1 protect these precursor cells from apoptosis, and this effect is mainly mediated by IRS-1 111.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Tseng, Y. H., Ueki, K., Kriauciunas, K. M. & Kahn, C. R. Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. J. Biol. Chem. 277, 31601–31611 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transgenic mice overexpressing FGF-19 have increased BAT mass and reduced susceptibility to diet-induced obesity.

    “Transgenic mice overexpressing FGF-19 have increased BAT mass and reduced susceptibility to diet-induced obesity 105.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Tomlinson, E. et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 143, 1741–1747 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BMP-7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage and also plays a critical role in embryonic brown fat development, as exemplified by the BMP-7 knockout embryo that shows a marked paucity of brown fat and near complete absence of UCP1.

    “Moreover, BMP-7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage and also plays a critical role in embryonic brown fat development, as exemplified by the BMP-7 knockout embryo that shows a marked paucity of brown fat and near complete absence of UCP1 101.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Tseng, Y. H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008). This paper identifies BMP7 as an inducer of brown adipocyte differentiation, and demonstrates that adenoviral-mediated expression of BMP7 in mice leads to increased brown fat-mediated energy expenditure and reduced weight gain. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Disruption of the klotho gene in mice results in almost complete absence of WAT, while BAT is present but reduced in size and UCP1 protein expression; these mice also have lower core body temperature.

    “Disruption of the klotho gene in mice results in almost complete absence of WAT, while BAT is present but reduced in size and UCP1 protein expression. These mice also have lower core body temperature 108.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Mori, K. et al. Disruption of klotho gene causes an abnormal energy homeostasis in mice. Biochem. Biophys. Res. Commun. 278, 665–670 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    bFGF stimulates the growth of brown fat precursors and may contribute to cold-induced enlargement of brown fat via an autocrine mechanism.

    “bFGF stimulates the growth of brown fat precursors and may contribute to cold-induced enlargement of brown fat via an autocrine mechanism 103.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Yamashita, H. et al. Basic fibroblast growth factor (bFGF) contributes to the enlargement of brown adipose tissue during cold acclimation. Pflugers Arch. 428, 352–356 (1994). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adenoviral-mediated expression of BMP-7 in mice results in a significant increase in brown, but not white, fat mass and leads to an increase in energy expenditure and reduced weight gain.

    “Adenoviral-mediated expression of BMP-7 in mice results in a significant increase in brown, but not white, fat mass and leads to an increase in energy expenditure and reduced weight gain 101.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Tseng, Y. H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008). This paper identifies BMP7 as an inducer of brown adipocyte differentiation, and demonstrates that adenoviral-mediated expression of BMP7 in mice leads to increased brown fat-mediated energy expenditure and reduced weight gain. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The development of fully functional brown adipocytes can be divided into three phases: a commitment phase, a differentiation phase and an activation phase.

    “The development of fully functional brown adipocytes can be divided into three phases: a “commitment phase”, a “differentiation phase” and an “activation phase” (Figure 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Figure 3

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, interscapular BAT is only a transient phenomenon in newborns and is replaced in adults by BAT in the neck and other anatomical locations.

    “In humans, interscapular BAT is only a transient phenomenon in newborns 96 and is replaced in adults by BAT in the neck and other anatomical locations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Lean, M. E. J. & James, W. P. T. in Brown Adipose Tissue (eds Trayhurn, P. & Nicholls, D. G.) 339–365 (Edward Arnold, London, 1986).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    It is possible that some UCP1 positive brown fat cells found in WAT or skeletal muscle come from transdifferentiation of white adipocytes.

    “It is also possible that some UCP1 positive brown fat cells found in WAT or skeletal muscle come from transdifferentiation of white adipocytes 94.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Cinti, S. Transdifferentiation properties of adipocytes in the adipose organ. Am. J. Physiol. Endocrinol. Metab. 297, E977–E986 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Up to 50% of the increase in metabolism in lean men induced by ephedrine is attributable to skeletal muscle, and 24% is contributed by BAT.

    “Astrup et al. estimated that up to 50% of the increase in metabolism in lean men induced by ephedrine is attributable to skeletal muscle, and 24% is contributed by BAT 119.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] Astrup, A., Bulow, J., Madsen, J. & Christensen, N. J. Contribution of BAT and skeletal muscle to thermogenesis induced by ephedrine in man. Am. J. Physiol. 248, E507–E515 (1985).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A meta-analysis of several dozen trials showed that ephedrine promotes modest short-term weight loss, but there are no data on longer-term efficacy.

    “A meta-analysis of several dozen trials showed that ephedrine promotes modest short-term weight loss, but there are no data on longer-term efficacy 134.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Shekelle, P. G. et al. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA 289, 1537–1545 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ephedrine is a mixed sympathomimetic capable of directly activating both α and β adrenergic receptors and enhancing release of norepinephrine from sympathetic neurons.

    “Ephedrine is a mixed sympathomimetic capable of directly activating both α and β adrenergic receptors and enhancing release of norepinephrine from sympathetic neurons 118.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] Nelson, D. L. & Gehlert, D. R. Central nervous system biogenic amine targets for control of appetite and energy expenditure. Endocrine 29, 49–60 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adult human BAT is functional and may be involved in protecting against weight loss.

    “Although it has only recently been proven that adult human BAT is functional and may be involved in protecting against weight loss 13–17, attempts to exploit BAT energy expenditure for treating obesity have been around for decades.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [13] Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009). source

      Not checked in the free run.

    • cites [14] Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009). source

      Not checked in the free run.

    • cites [15] Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009). source

      Not checked in the free run.

    • cites [16] Saito, M. et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58, 1526–1531 (2009). source

      Not checked in the free run.

    • cites [17] Zingaretti, M. C. et al. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J. 23, 3113–3120 (2009). References 13–17 report the rediscovery of metabolically active brown fat in adult humans using non-invasive PET and CT scans coupled with immunohistochemistry, electron microscopy, and gene and protein expression assays. These led to the consideration that brown fat may play a role in normal physiology and could be a target for obesity treatment. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    BMP-7 is a multifunctional cytokine and has been implicated as a potential therapeutic agent for cardiovascular, metabolic, and degenerative diseases, mostly validated in mouse models.

    “Originally identified as a bone inducer, BMP-7 is now being recognized as a multifunctional cytokine and has been implicated as a potential therapeutic agent for cardiovascular, metabolic, and degenerative diseases as mostly validated in mouse models 122.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Tobin, J. F. & Celeste, A. J. Bone morphogenetic proteins and growth differentiation factors as drug targets in cardiovascular and metabolic disease. Drug Discov. Today 11, 405–411 (2006). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    With the recognition that adult humans have BAT, targeting cellular bioenergetics has become an increasingly attractive way to dissipate excess energy and provide a potential therapeutic approach for the treatment or prevention of obesity and associated diseases.

    “With the recognition that adult humans have brown adipose tissue, targeting cellular bioenergetics has become an increasingly attractive way to dissipate excess energy and provide a potential therapeutic approach for the treatment or prevention of obesity and it associated diseases.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Obesity is a growing worldwide epidemic and new effective anti-obesity therapies are needed.

  • May combine two claims.

    Premisecitation

    Thyroid hormone increases thermogenesis and promotes formation of less oxidative fibers.

    “On the other hand, thyroid hormone, which also increases thermogenesis, promotes formation of less oxidative fibers 46, indicating that different physiological stimuli regulate thermogenesis in muscle by different mechanisms.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Himms-Hagen, J. Exercise in a pill: feasibility of energy expenditure targets. Curr. Drug Targets CNS Neurol. Disord. 3, 389–409 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mild cold exposure at 16 °C induces muscle mitochondrial uncoupling and increases energy expenditure via NST.

    “Mild cold exposure (16 °C) also induces muscle mitochondrial uncoupling and increases energy expenditure via NST 45.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Wijers, S. L., Schrauwen, P., Saris, W. H. & Marken Lichtenbelt, W. D. Human skeletal muscle mitochondrial uncoupling is associated with cold induced adaptive thermogenesis. PLoS ONE 3, e1777 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Up to 250 kcal per hour are consumed by shivering.

    “Up to 250 kcal per hour are consumed by shivering 113, but this response is highly variable, usually of short duration, and not a likely method for therapeutic intervention.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Badjatia, N. et al. Predictors and clinical implications of shivering during therapeutic normothermia. Neurocrit. Care 6, 186–191 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endurance exercise training triggers remodeling of skeletal muscle by increasing expression of genes involved in mitochondrial respiration and fatty acid oxidation, which helps protect against obesity and related metabolic disorders.

    “Endurance exercise training triggers a remodeling of skeletal muscle by increasing expression of genes involved in mitochondrial respiration and fatty acid oxidation, which helps protect against obesity and related metabolic disorders 114.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Goodyear, L. J. The exercise pill — too good to be true? N. Engl. J. Med. 359, 1842–1844 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ephedra contains alkaloids ephedrine, pseudoephedrine, and other sympathomimetics that can induce central nervous system stimulation, bronchodilation, and vasoconstriction.

    “Among its myriad of chemical compounds, ephedra contains the alkaloids ephedrine, pseudoephedrine, and other sympathomimetics that can induce central nervous system stimulation, bronchodilation, and vasoconstriction 118.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] Nelson, D. L. & Gehlert, D. R. Central nervous system biogenic amine targets for control of appetite and energy expenditure. Endocrine 29, 49–60 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Shivering thermogenesis is highly variable, usually of short duration, and not a likely method for therapeutic intervention.

    “Up to 250 kcal per hour are consumed by shivering 113, but this response is highly variable, usually of short duration, and not a likely method for therapeutic intervention.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Badjatia, N. et al. Predictors and clinical implications of shivering during therapeutic normothermia. Neurocrit. Care 6, 186–191 (2007). source

      Not checked in the free run.

    • Rests on an assumption: Shivering thermogenesis occurs in muscle and complements non-shivering thermogenesis, which occurs primarily in BAT in response to cold.

  • May combine two claims.

    Interpretationcitation

    TGR5 can theoretically protect against obesity and its complications via two distinct and potentially synergistic mechanisms: increased energy expenditure and improved insulin sensitivity.

    “TGR5 is therefore a new and attractive target for treating obesity, since it can theoretically protect against obesity and its complications via two distinct and potentially synergistic mechanisms: increased energy expenditure and improved insulin sensitivity 148.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [148] Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell. Metab. 10, 167–177 (2009). This paper reports that the compound INT-777, a selective agonist of the TGR5 receptor, induces intestinal GLP1 release and leads to improved liver and pancreatic function. source

      Not checked in the free run.

    • Rests on an assumption: TGR5 stimulates GLP-1 production in enteroendocrine cells, improving glucose metabolism through insulinotropic effects.

  • Classified as probably not a substantial claim.

    Premisecitation

    Exercise has numerous health benefits.

    “Given the numerous health benefits of exercise, the idea of a pill that mimics the effects of exercise is very attractive 46, especially in individuals with physical limitations in exercising or those who are genetically predisposed to obesity 114.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Himms-Hagen, J. Exercise in a pill: feasibility of energy expenditure targets. Curr. Drug Targets CNS Neurol. Disord. 3, 389–409 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BAT is not a simple combustion engine, but an exquisitely regulated biological tissue with internal negative feedback pathways.

    “Fortunately, BAT is not a simple combustion engine, but an exquisitely regulated biological tissue with internal negative feedback pathways 30,30.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Golozoubova, V. et al. Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. FASEB J. 15, 2048–2050 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effect of bile acids on energy expenditure is dependent on induction of type 2 iodothyronine deiodinase and mediated by binding to TGR5.

    “Bile acids also increase energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This effect is dependent on induction of the type 2 iodothyronine deiodinase and is mediated by the binding of bile acids to a novel G-protein-coupled receptor TGR5 148.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [148] Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell. Metab. 10, 167–177 (2009). This paper reports that the compound INT-777, a selective agonist of the TGR5 receptor, induces intestinal GLP1 release and leads to improved liver and pancreatic function. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Leptin deficiency is rare in humans, and most obese humans suffer from leptin resistance, so administration of leptin shows effects in only a small fraction of patients.

    “However, leptin deficiency is rare in humans, and most obese humans suffer from leptin resistance,, so administration of leptin shows effects in only a small fraction of patients 151.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [151] Friedman, J. M. Leptin at 14 y of age: an ongoing story. Am. J. Clin. Nutr. 89, 973S–979S (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rodents, the β3-adrenergic receptor is found nearly exclusively on brown adipocytes, and treatment with the β3-specific agonist CL-316,243 substantially increases energy expenditure.

    “In rodents, the β3-adrenergic receptor is found nearly exclusively on brown adipocytes, and treatment with the β3-specific agonist CL-316,243 substantially increases energy expenditure 18.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Harper, M. E., Green, K. & Brand, M. D. The efficiency of cellular energy transduction and its implications for obesity. Annu. Rev. Nutr. 28, 13–33 (2008). This comprehensive review discusses bioenergetics and the reasons for targeting uncoupling for the treatment of obesity. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bile acids increase energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin.

    “Bile acids also increase energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This effect is dependent on induction of the type 2 iodothyronine deiodinase and is mediated by the binding of bile acids to a novel G-protein-coupled receptor TGR5 148.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [148] Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell. Metab. 10, 167–177 (2009). This paper reports that the compound INT-777, a selective agonist of the TGR5 receptor, induces intestinal GLP1 release and leads to improved liver and pancreatic function. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One TGR5 agonist, INT-777, has shown efficacy in vivo, increasing energy expenditure and reducing adiposity in mice with diet-induced obesity.

    “One promising TGR5 agonist, INT-777, has already shown efficacy in vivo, increasing energy expenditure and reducing adiposity in mice with diet-induced obesity 148,149.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [148] Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell. Metab. 10, 167–177 (2009). This paper reports that the compound INT-777, a selective agonist of the TGR5 receptor, induces intestinal GLP1 release and leads to improved liver and pancreatic function. source

      Not checked in the free run.

    • cites [149] Tiwari, A. & Maiti, P. TGR5: an emerging bile acid G-protein-coupled receptor target for the potential treatment of metabolic disorders. Drug Discov. Today 14, 523–530 (2009). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Caffeine is a trimethylxanthine that inhibits adenosine A2A receptors, thus stimulating the central nervous system and reducing the perception of fatigue.

    “Caffeine is a trimethylxanthine that inhibits adenosine A2A receptors 137, thus stimulating the central nervous system and reducing the perception of fatigue.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Huang, Z. L. et al. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nature Neurosci. 8, 858–859 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The combination of ephedrine and caffeine is a potent mediator of short-term weight loss that likely involves activation of BAT by β3 adrenergic receptors.

    “However, the combination of ephedrine and caffeine is a potent mediator of short-term weight loss 139 that likely involves activation of BAT by β3 adrenergic receptors 140.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [139] Boozer, C. N. et al. Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial. Int. J. Obes. Relat Metab. Disord. 26, 593–604 (2002). source

      Not checked in the free run.

    • cites [140] De Matteis, R. et al. Immunohistochemical identification of the β3-adrenoceptor in intact human adipocytes and ventricular myocardium: effect of obesity and treatment with ephedrine and caffeine. Int. J. Obes. Relat Metab. Disord. 26, 1442–1450 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Leptin both decreases appetite and increases energy expenditure and is able to completely reverse obesity in the leptin-deficient ob/ob mouse.

    “The adipokine leptin both decreases appetite and increases energy expenditure and is able to completely reverse obesity in the leptin-deficient ob/ob mouse 150.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Given the new ability to quantify human BAT activity, attempts at therapeutically developing β3-adrenergic agonists and other drugs that activate BAT or stimulate BAT growth require re-evaluation.

    “Given the new ability to quantify human brown adipose tissue activity, attempts at therapeutically developing β3-adrenergic agonists and other drugs that activate BAT or stimulate BAT growth requires re-evaluation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    AMPK detects the nutrient status of the cell and helps regulate glucose transport, fatty acid oxidation, and metabolic adaptations in skeletal muscle.

    “Another enzyme central to cellular bioenergetics is AMP-activated protein kinase (AMPK), which detects the nutrient status of the cell and helps regulate glucose transport, fatty acid oxidation, and metabolic adaptations in skeletal muscle 159.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [159] Koh, H. J., Brandauer, J. & Goodyear, L. J. LKB1 and AMPK and the regulation of skeletal muscle metabolism. Curr. Opin. Clin. Nutr. Metab. Care 11, 227–232 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNP, a non-selective uncoupler of mitochondrial oxidation, at 3-5 mg/kg, in humans led to a 20-30% increase in energy expenditure that could be sustained without tolerance.

    “DNP, a non-selective uncoupler of mitochondrial oxidation, at 3–5 mg/kg, in humans led to a 20–30% increase in energy expenditure that could be sustained without tolerance 18.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Harper, M. E., Green, K. & Brand, M. D. The efficiency of cellular energy transduction and its implications for obesity. Annu. Rev. Nutr. 28, 13–33 (2008). This comprehensive review discusses bioenergetics and the reasons for targeting uncoupling for the treatment of obesity. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Resveratrol treatment leads to increased lifespan and improved metabolic profile and activity levels in mice with high fat diet-induced obesity.

    “Resveratrol treatment leads to increased lifespan and improved metabolic profile and activity levels in mice with high fat diet-induced obesity 156.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Resveratrol can improve exercise endurance and protect mice against diet-induced obesity and insulin resistance.

    “Resveratrol (3,5,4'-trihydroxystilbene), a polyphenol found in grape skins, red wine, peanuts, and mulberries, can improve exercise endurance and protect mice against diet-induced obesity and insulin resistance 155.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [155] Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Due to high safety concerns for anti-obesity treatments, both the conventional pharmaceutical approach and the cell-based therapy require intensive benefit-risk assessments.

    “However, due to the high safety concerns for anti-obesity treatments, both the conventional pharmaceutical approach and the cell-based therapy require intensive benefit-risk assessments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The effect of PRDM16 depends on interaction with PGC-1α/β, PPARγ and C/EBPβ, while binding to CtBP-1 and CtBP-2 suppresses expression of white fat-selective genes.

    “This effect depends on the interaction of PRDM16 with PGC-1α/β, PPARγ and C/EBPβ, while binding of PRDM16 to CtBP-1 and CtBP-2 suppresses expression of white fat-selective genes 171,172.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [171] Kajimura, S. et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes. Dev. 22, 1397–1409 (2008). source

      Not checked in the free run.

    • cites [172] Kajimura, S. et al. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-β transcriptional complex. Nature 460, 1154-1158 (2009). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    If safety can be proven, increasing mitochondrial uncoupling may represent a potential therapeutic approach.

    “However, if safety can be proven, increasing mitochondrial uncoupling may represent a potential therapeutic approach.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Increased mitochondrial uncoupling leads to energy inefficiency and increased energy expenditure.

  • May combine two claims.

    Premisecitation

    Nuclear co-repressor RIP140 directs histone and DNA methylation to silence UCP1 expression and suppress mitochondrial biogenesis in white adipocytes.

    “Nuclear co-repressor RIP140 directs histone and DNA methylation to silence UCP1 expression and suppress mitochondrial biogenesis in white adipocytes 169,170.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [169] Kiskinis, E. et al. RIP140 directs histone and DNA methylation to silence Ucp1 expression in white adipocytes. EMBO J. 26, 4831–4840 (2007). source

      Not checked in the free run.

    • cites [170] Powelka, A. M. et al. Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes. J. Clin. Invest. 116, 125–136 (2006). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation

    The safety issue of using AICAR or other drugs targeting AMPK needs to be considered.

    “While these data suggest a potential use of these compounds in improving skeletal muscle function and increasing energy expenditure, the safety issue of using AICAR or other drugs targeting AMPK needs to be considered 162.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Ruderman, N. B., Saha, A. K. & Kraegen, E. W. Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology 144, 5166–5171 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in deacetylation and modulation of downstream SIRT1 targets.

    “Recent studies show that AMPK also enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets 160.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Canto, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A new class of molecules that includes butylated hydroxytoluene utilizes the mitochondrial adenine nucleotide translocase to induce limited uncoupling at low concentrations and can have a dynamic range of more than a million fold in vitro.

    “A new class of molecules that includes butylated hydroxytoluene utilizes the mitochondrial adenine nucleotide translocase to induce limited uncoupling at low concentrations and can have a dynamic range of more than a million fold in vitro.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [164] Lou, P. H. et al. Mitochondrial uncouplers with an extraordinary dynamic range. Biochem. J. 407, 129–140 (2007). source

      Not checked in the free run.

86 of 86

  • The paper relies on this without support.

    Obesity develops when energy intake exceeds energy expenditure.

    “Obesity develops when energy intake exceeds energy expenditure.”
    “Obesity develops when energy intake exceeds energy expenditure.”

  • The paper relies on this without support.

    Any treatment for obesity must reduce energy intake, increase energy expenditure, or have an effect on both.

    “Since the laws of thermodynamics must be obeyed, any treatment for obesity must reduce energy intake, increase energy expenditure, or have an effect on both.”

  • The authors state this as an assumption.

    The laws of thermodynamics must be obeyed.

    “Since the laws of thermodynamics must be obeyed, any treatment for obesity must reduce energy intake, increase energy expenditure, or have an effect on both.”

  • The paper relies on this without support.

    Obesity is a growing worldwide epidemic and new effective anti-obesity therapies are needed.

    “With the growing worldwide epidemic of obesity, it is clear that new and effective anti-obesity therapies are desperately needed.”

  • The paper relies on this without support.

    Exercise has profound beneficial effects on virtually all biological systems and is an effective way to burn excess energy.

    “There is no doubt that exercise has profound beneficial effects on virtually all biological systems, and is an effective way to burn excess energy.”

  • The paper relies on this without support.

    Findings from mouse models of obesity and thermogenesis are predictive of human therapeutic outcomes.

    “When systemically expressed in mice, BMP-7 leads to reduced weight gain 101, suggesting that it may have anti-obesity potential, although more study is needed to determine an optimal therapeutic approach and if there will be any unwanted side effects.”

  • The paper relies on this without support.

    TGR5 stimulates GLP-1 production in enteroendocrine cells, improving glucose metabolism through insulinotropic effects.

    “In addition, TGR5 stimulates GLP-1 production in enteroendocrine cells that may improve glucose metabolism through its insulinotropic effects.”

  • The paper relies on this without support.

    Preclinical observations suggest that resveratrol and its analogues such as SRT1720 are safe and may have applications in the treatment of obesity and insulin resistance in humans.

    “Preclinical observations have suggested that resveratrol and its analogues such as SRT1720 are safe and may have applications in the treatment of obesity and insulin resistance in humans.”

  • The paper relies on this without support.

    Increased mitochondrial uncoupling leads to energy inefficiency and increased energy expenditure.

    “Increased mitochondrial uncoupling leads to energy inefficiency and increased energy expenditure.”

  • The paper relies on this without support.

    BMP-7 is pharmaceutically available and already in use for orthopedic procedures in the US under Humanitarian Device Exemptions.

    “BMP-7 is pharmaceutically available and is already in use for orthopedic procedures in the US under Humanitarian Device Exemptions.”

  • The paper relies on this without support.

    Shivering thermogenesis occurs in muscle and complements non-shivering thermogenesis, which occurs primarily in BAT in response to cold.

    “Shivering thermogenesis occurs in muscle and complements non-shivering thermogenesis, which occurs primarily in BAT in response to cold.”

  • The paper relies on this without support.

    Three types of thermogenesis occur in skeletal muscle: exercise-induced thermogenesis, NEAT, and cold-induced shivering thermogenesis.

    “Three types of thermogenesis occur in skeletal muscle: exercise-induced thermogenesis, non-exercise activity thermogenesis (NEAT), and cold-induced shivering thermogenesis (ST).”

  • The paper relies on this without support.

    Another important mechanism for heat production in skeletal muscle involves ATP turnover and maintenance of the calcium gradient mediated by SERCA proteins.

    “Another important mechanism for heat production in skeletal muscle involves ATP turnover and maintenance of the calcium gradient mediated by the sarcoplasmic reticulum calcium ATPases (SERCA proteins) (Figure 2c).”
13 of 13

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The principal cause of obesity is energy imbalance: calories consumed exceed calories utilized by bodily processes.

    “The principal cause of obesity is energy imbalance: the calories consumed are greater than that utilized by bodily processes, e.g., breathing, digestion, thermogenesis [7].”

    From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [7]

  • Weight loss via caloric restriction faces difficulties including an evolution-engendered guard against low fat mass and a propensity to increase caloric efficiency during dieting.

    “Even weight loss via caloric restriction faces difficulties, including an evolution-engendered guard against low fat mass [7, 31] and the propensity of the body to increase caloric efficiency during dieting [32, 33].”

    From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [7]

  • BMR includes cellular turnover, repair and basic functions, basal synthetic reactions, mitochondrial proton leak, and obligatory thermogenesis.

    “BMR includes cellular turnover, repair and basic functions (e.g., maintenance of ion gradients, transmembrane metabolite transfer), basal synthetic reactions (e.g., RNA, DNA protein synthesis) and mitochondrial proton leak; it also includes obligatory thermogenesis (e.g., digestion and absorption) [7, 46].”

    From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [7]

  • Activation of UCP1 uncouples aerobic respiration by producing heat instead of ATP.

    “Activation of this protein uncouples aerobic respiration by producing heat instead of ATP ([162](#B162)).”

    From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [162]

  • BAT thermogenesis takes place in its numerous, densely packed mitochondria, which contain BAT-specific UCP1.

    “BAT thermogenesis takes place in its numerous, densely packed mitochondria, which contain the BAT-specific UCP1.”

    From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [162]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Adult human BAT is described in two different locations

    Minor

    The first statement places adult human BAT between the shoulder blades; the next places its most common location in the neck. The first statement appears to have meant BAT in rodents and human babies, but as written the two conflict.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Neumann, R. O. Experimentelle Beitrage Zur Lehre von den taglichen Nahrungsbedarf des Menschen unter besonderer Bernuksichtigung der notwendigen Eiweissmenge. Archiv fur Hygeine 45, 1–87 (1902) (in German).

Cited by

Sorted by citations

Related

Authors
Tseng, Y.-H., Cypess, A. M., & Kahn, C. R.
Affiliations
Joslin Diabetes Center (US)
Corresponding author
  • Tseng, Yu-Hua
  • Kahn, C. Ronald
ORCID
Venue
Nature Reviews Drug Discovery
Publisher
Springer Science and Business Media LLC
Published
2010-06
Volume
9
Issue
6
Pages
465-482
ISSN
  • 1474-1776 (ISSN-L)
  • 1474-1784
DOI
10.1038/nrd3138
PMC
PMC2880836
OpenAlex
W2057337991
Semantic Scholar
15bac6900395e592dd9480d2e9f5ed3821e8483c
Cited by
591
References
208
Citations by year
2026: 11 · 2025: 18 · 2024: 16 · 2023: 32 · 2022: 35 · 2021: 37 · 2020: 31 · 2019: 46 · 2018: 37 · 2017: 53 · 2016: 43 · 2015: 53 · 2014: 67 · 2013: 40 · 2012: 43
FWCI
3.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Drug Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK077097, DK-082659, K23DK081604, P30DK046200, DK046200, DK077097, DK081604, P30DK036836, R01DK082659)
  • National Center for Research Resources (UL1RR025758, KL2RR025757, RR025758, RR025757)
Topics
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
obesity treatment, cellular bioenergetics, energy expenditure, adaptive thermogenesis, brown adipose tissue, skeletal muscle thermogenesis, anti-obesity drugs, energy balance
MeSH terms
Uncoupling Protein 1, Adenosine Triphosphate, Adipose Tissue, Brown, Energy Metabolism, Humans, Ion Channels, Mitochondria, Obesity, Transforming Growth Factor beta, Cell Lineage, Thermogenesis, Mitochondrial Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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