Cellular bioenergetics as a target for obesity therapy

In the paper

“However, because of the unacceptable side effects or inadequate long-term clinical efficacy, these medications have thus far met limited success 7.”

What the sources say

• Not checked yetcites [7] Melnikova, I. & Wages, D. Anti-obesity therapies. Nature Rev. Drug Discov. 5, 369–370 (2006). source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [5] Kaplan, L. M. Pharmacological therapies for obesity. Gastroenterol. Clin. North Am. 34, 91–104 (2005). source

In the paper

“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.”

What the sources say

• Not checked yetcites [3] Lowell, B. B. & Spiegelman, B. M. Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652–660 (2000). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [21] Chow, C. C. & Hall, K. D. The dynamics of human body weight change. PLoS Comput. Biol. 4, e1000045 (2008). source

In the paper

“For example, dinitrophenol (DNP), a non-selective uncoupler of mitochondrial oxidation, effectively increases energy expenditure that could be sustained without tolerance 18.”

What the sources say

• Not checked yetcites [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

In the paper

“UCP1 is unique to BAT and is necessary to mediate BAT thermogenesis 30.”

What the sources say

• Not checked yetcites [30] Golozoubova, V. et al. Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. FASEB J. 15, 2048–2050 (2001). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [15] Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009). source
• Not checked yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [8] Wells, J. C. Thrift: a guide to thrifty genes, thrifty phenotypes and thrifty norms. Int. J. Obes. (Lond.) 33, 1331–1318 (2009). source
• Not checked yetcites [9] Speakman, J. R. A nonadaptive scenario explaining the genetic predisposition to obesity: the “predation release” hypothesis. Cell. Metab. 6, 5–12 (2007). source

In the paper

“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).”

What the sources say

• Not checked yetcites Box 1
• Not checked yetcites Figure 2a

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

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

What the sources say

• Not checked yetcites Figure 1

In the paper

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

What the sources say

• Not checked yetcites Figure 1

In the paper

“Newborn human infants cannot shiver, and thus maintenance of body temperature depends entirely on NST by brown fat 47.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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
• Not checked yetcites [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

In the paper

“Conversely, ablation of BAT leads to reduced energy expenditure and increased obesity on high fat diet 75.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [65] Silva, J. E. Thermogenic mechanisms and their hormonal regulation. Physiol. Rev. 86, 435–464 (2006). source

In the paper

“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.”

What the sources say

• Not checked yetcites [63] Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [85] Ravussin, E. & Kozak, L. P. Have we entered the brown adipose tissue renaissance? Obes. Rev. 10, 265–268 (2009). source

In the paper

“Thus, UCP1-ablated mice are more susceptible to cold and have to rely on shivering for thermoregulation 31.”

What the sources say

• Not checked yetcites [31] Enerback, S. et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 90–94 (1997). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [69] Harris, R. B. Leptin — much more than a satiety signal. Annu. Rev. Nutr. 20, 45–75 (2000). source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [77] Astrup, A. Thermogenesis in human brown adipose tissue and skeletal muscle induced by sympathomimetic stimulation. Acta Endocrinol. Suppl. (Copenh.) 278, 1–32 (1986).
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [71] Ferrannini, E. et al. Insulin: new roles for an ancient hormone. Eur. J. Clin. Invest. 29, 842–852 (1999). source

In the paper

“Induction of BAT in mice promotes energy expenditure, reduces adiposity, and protects mice from diet-induced obesity 73,74.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Adipose tissue is generally considered to arise from the multipotent mesenchymal stem cells of mesodermal origin 89.”

What the sources say

• Not checked yetcites [89] Gesta, S., Tseng, Y. H. & Kahn, C. R. Developmental origin of fat: tracking obesity to its source. Cell 131, 242–256 (2007). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“More importantly, BAT activity correlates inversely with BMI13,14 and percentage body fat 13,14, suggesting a role in energy balance.”

What the sources say

• Not checked yetcites [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 yetcites [14] Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“PET/CT positivity shows seasonal variation 13,16,88, indicating a role of BAT in normal adaptation to cold.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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).

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [14] Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009). source

In the paper

“While BMP-2 and 4 promote white fat differentiation, BMP-7 serves as a potent inductive signal for brown adipogenesis 101.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [107] Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115, 1627–1635 (2005). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“BMPs are a family of developmental regulators belonging to the TGF-β superfamily, which promote adipogenesis at different stages 100.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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 yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“Both insulin and IGF-1 protect these precursor cells from apoptosis, and this effect is mainly mediated by IRS-1 111.”

What the sources say

• Not checked yetcites [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

In the paper

“Transgenic mice overexpressing FGF-19 have increased BAT mass and reduced susceptibility to diet-induced obesity 105.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“bFGF stimulates the growth of brown fat precursors and may contribute to cold-induced enlargement of brown fat via an autocrine mechanism 103.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites Figure 3

In the paper

“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.”

What the sources say

• Not checked yetcites [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).

In the paper

“It is also possible that some UCP1 positive brown fat cells found in WAT or skeletal muscle come from transdifferentiation of white adipocytes 94.”

What the sources say

• Not checked yetcites [94] Cinti, S. Transdifferentiation properties of adipocytes in the adipose organ. Am. J. Physiol. Endocrinol. Metab. 297, E977–E986 (2009). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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).

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Ephedrine is a mixed sympathomimetic capable of directly activating both α and β adrenergic receptors and enhancing release of norepinephrine from sympathetic neurons 118.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [15] Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009). source
• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [46] Himms-Hagen, J. Exercise in a pill: feasibility of energy expenditure targets. Curr. Drug Targets CNS Neurol. Disord. 3, 389–409 (2004). source

In the paper

“Mild cold exposure (16 °C) also induces muscle mitochondrial uncoupling and increases energy expenditure via NST 45.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [113] Badjatia, N. et al. Predictors and clinical implications of shivering during therapeutic normothermia. Neurocrit. Care 6, 186–191 (2007). source

In the paper

“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.”

What the sources say

• Not checked yetcites [114] Goodyear, L. J. The exercise pill — too good to be true? N. Engl. J. Med. 359, 1842–1844 (2008). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [113] Badjatia, N. et al. Predictors and clinical implications of shivering during therapeutic normothermia. Neurocrit. Care 6, 186–191 (2007). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [46] Himms-Hagen, J. Exercise in a pill: feasibility of energy expenditure targets. Curr. Drug Targets CNS Neurol. Disord. 3, 389–409 (2004). source

In the paper

“Fortunately, BAT is not a simple combustion engine, but an exquisitely regulated biological tissue with internal negative feedback pathways 30,30.”

What the sources say

• Not checked yetcites [30] Golozoubova, V. et al. Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. FASEB J. 15, 2048–2050 (2001). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [151] Friedman, J. M. Leptin at 14 y of age: an ongoing story. Am. J. Clin. Nutr. 89, 973S–979S (2009). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Caffeine is a trimethylxanthine that inhibits adenosine A2A receptors 137, thus stimulating the central nervous system and reducing the perception of fatigue.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [150] Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994). source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Resveratrol treatment leads to increased lifespan and improved metabolic profile and activity levels in mice with high fat diet-induced obesity 156.”

What the sources say

• Not checked yetcites [156] Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“However, if safety can be proven, increasing mitochondrial uncoupling may represent a potential therapeutic approach.”

In the paper

“Nuclear co-repressor RIP140 directs histone and DNA methylation to silence UCP1 expression and suppress mitochondrial biogenesis in white adipocytes 169,170.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [160] Canto, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009). source

In the paper

“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.”

What the sources say

• Not checked yetcites [164] Lou, P. H. et al. Mitochondrial uncouplers with an extraordinary dynamic range. Biochem. J. 407, 129–140 (2007). source