Exercise in a Pill: Feasibility of Energy Expenditure Targets
Abstract
The possibility of developing a pill to increase energy expenditure is explored by examining the metabolic processes involved. Such a pill should be targeted at organ systems involved in facultative thermogenesis. In rodents, these are brown adipose tissue (BAT) and skeletal muscle. Since BAT-mediated thermogenesis is not available in adult humans, emphasis here is on skeletal muscle. A hypothesis is presented based on three known facts: (1) plasticity of skeletal muscle, with interconversion of fiber types that differ in their fuel efficiency; (2) presence of thyroxine 5'-deiodinase type 2 (TD2) in human skeletal muscle; (3) gradual increase in thermogenesis that occurs during rehabilitation after starvation, probably in muscle. A low capacity thermogenic system, muscle efficiency thermogenesis (MET), is proposed to occur as adipose stores refill during the transition from famine to feasting to obesity. This system involves increased activity of TD2 and a T3-induced increase in proportion of type II fibers, less efficient at rest and during activity. The protective effect of this system is probably overwhelmed by long-term eating in excess of energy needs. Better understanding of the complex remodeling of differentiated muscle fibers in the conversions proposed and of the regulation of TD2 activity in human skeletal muscle may reveal targets for increasing energy expenditure in humans. In addition, the possibility of exploiting the plasticity of the adipose organ, with conversion of white adipocytes in white adipose tissue to atypical brown adipocytes and increasing thermogenesis in them is considered as another potential target for increasing energy expenditure in humans.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
During prolonged cold exposure of rodents and humans, even as shivering disappears, energy expenditure remains elevated due to NST.
“During prolonged cold exposure of rodents and humans, even as shivering disappears, energy expenditure remains elevated, due to NST 46.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [46]
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.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [46]
Different physiological stimuli regulate thermogenesis in muscle by different mechanisms.
“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.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [46]
Skeletal muscle is an important organ for thermogenesis.
“After BAT, skeletal muscle is the other important organ for thermogenesis 46.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [46]
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.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [46]
Cited by
Sorted by citations
Fuller, N. R., Colagiuri, S., SCHOFIELD, D. J., Olson, A. D., Shrestha, R. N., Holzapfel, C., Wolfenstetter, S. B., Holle, R., Ahern, A. L., Hauner, H., et al. (2012) · International Journal of Obesity · doi:10.1038/ijo.2012.139 · Cited by 2,125 · see citing works
Cellular bioenergetics as a target for obesity therapy
Tseng, Y.-H., Cypess, A. M., & Kahn, C. R. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3138 · Cited by 591 · see citing works
“During prolonged cold exposure of rodents and humans, even as shivering disappears, energy expenditure remains elevated due to non-shivering thermogenesi”
BackgroundSubcutaneous fat in normal and diseased states
Avram, M. M., Avram, A. S., & James, W. D. (2007) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2006.06.022 · Cited by 266 · see citing works
UCP1-independent Thermogenesis in White Adipose Tissue of Cold-acclimated Ucp1 -/- Mice
Ukropec, J., Anunciado, R. V. P., Ravussin, Y., Hulver, M. W., & Kozak, L. P. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m606114200 · Cited by 284 · see citing works
Devenny, J. J., Godonis, H. E., Harvey, S. J., Rooney, S., Cullen, M. J., & Pelleymounter, M. A. (2012) · Obesity · doi:10.1038/oby.2012.59 · Cited by 212 · see citing works
“chronic effects of dapagliflozin (5 mpk) on urine volume and glucose excretion in dIo rats (Table 2) ANOVA revealed significant treatment effects on urine volume (F (2, 18) = 105.”
BackgroundMethodInfluentialSubcutaneous fat in normal and diseased states
Avram, A. S., Avram, M. M., & James, W. D. (2005) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2005.05.015 · Cited by 169 · see citing works
Emerging Therapeutic Strategies for Obesity
Foster‐Schubert, K. E., & Cummings, D. E. (2006) · Endocrine Reviews · doi:10.1210/er.2006-0041 · Cited by 139 · see citing works
“elsewhere (11) and are not a focus of this paper.”
BackgroundBlondin, D. P., Daoud, A., Taylor, T. R., Tingelstad, H. C., Bézaire, V., Richard, D., Carpentier, A. C., Taylor, A. W., Harper, M., Aguer, C., et al. (2016) · The Journal of Physiology · doi:10.1113/jp273395 · Cited by 134 · see citing works
“We hypothesized that perhaps a colder stimulus is required to observe the expected decrease in shivering activity that is typically seen in rodents (Himms-Hagen, 2004).”
BackgroundInfluentialImplications of exercise-induced adipo-myokines in bone metabolism
Lombardi, G., Sanchis‐Gomar, F., Perego, S., Sansoni, V., & Banfi, G. (2015) · Endocrine · doi:10.1007/s12020-015-0834-0 · Cited by 117 · see citing works
“Energy excess, as in obesity, induces the prevalence of type II muscular fibers, which display a low-efficiency energy usage profile [230].”
BackgroundQuinn, L. S., Anderson, B. G., Conner, J. D., & Wolden-Hanson, T. (2013) · Endocrinology · doi:10.1210/en.2012-1773 · Cited by 102 · see citing works
Current and Future Drug Targets in Weight Management
Witkamp, R. F. (2010) · Pharmaceutical Research · doi:10.1007/s11095-010-0341-1 · Cited by 78 · see citing works
“PYY PYY(3-36) analogues Nasal formulations, development discontinued for the time being”
BackgroundCaloric restriction and exercise “mimetics”: ready for prime time
Handschin, C. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2015.11.009 · Cited by 72 · see citing works
“The concept of designing pharmacological agents that engage the same or at least similar biological programs as bona fide training was initially focused on facultative energy expenditure [28].”
BackgroundSarcolemmal ATP-Sensitive K+ Channels Control Energy Expenditure Determining Body Weight
Alekseev, A. E., Reyes, S., Yamada, S., Hodgson‐Zingman, D., Sattiraju, S., Zhu, Z., Sierra, A., Marina Gerbin, B., Coetzee, W. A., Goldhamer, D. J., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2009.11.009 · Cited by 69 · see citing works
The Endogenous Actions of Hypothalamic Peptides on Brown Adipose Tissue Thermogenesis in the Rat
Verty, A. N. A., Allen, A. M., & Oldfield, B. J. (2010) · Endocrinology · doi:10.1210/en.2009-1235 · Cited by 59 · see citing works
Plasma concentrations of free triiodothyronine predict weight change in euthyroid persons
Ortega, E., Pannacciulli, N., Bogardus, C., & Krakoff, J. A. (2007) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/85.2.440 · Cited by 57 · see citing works
“Whether tissue-selective (specifically, muscle) modifications in deiodinase activity may be a suitable target for drug intervention remains unclear (56).”
BackgroundExercise Pills: At the Starting Line
Li, S., & Laher, I. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2015.08.014 · Cited by 54 · see citing works
“The concept of ‘exercise pills’ was first introduced by Himms-Hagen in 2004 [20], followed by Narkar and colleagues [14] who suggested that some molecules could mimic the effects of exercise training.”
BackgroundMolero, J. C., Waring, S. G., Cooper, A., Turner, N. A., Laybutt, D. R., Cooney, G. J., & James, D. E. (2006) · Diabetes · doi:10.2337/diabetes.55.03.06.db05-0312 · Cited by 46 · see citing works
“A key question arising from these studies is what causes the increased energy expenditure in the c-Cbl / mice? Brown adipose tissue and skeletal muscle have previously been described to be major regulators of whole-body energy expenditure in rodents (30).”
BackgroundCurrent trends and future prospects of lipstatin: a lipase inhibitor and pro-drug for obesity
Kumar, P., & Dubey, K. K. (2015) · RSC Advances · doi:10.1039/c5ra14892h · Cited by 38 · see citing works
Adaptations of Skeletal Muscle Mitochondria to Obesity, Exercise, and Polyunsaturated Fatty Acids
Chen, P. B., Yang, J. S., & Park, Y. (2018) · Lipids · doi:10.1002/lipd.12037 · Cited by 37 · see citing works
MOTS-c and Exercise Restore Cardiac Function by Activating of NRG1-ErbB Signaling in Diabetic Rats
Li, S., Wang, M., Ma, J., Pang, X., Yuan, J., Pan, Y., Fu, Y., & Laher, I. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.812032 · Cited by 36 · see citing works
Adipose tissue and skeletal muscle plasticity modulates metabolic health
Ukropec, J., Ukropcová, B., Kurdiová, T., Gašperíková, D., & Klimeś, I. (2008) · Archives of Physiology and Biochemistry · doi:10.1080/13813450802535812 · Cited by 33 · see citing works
Translational Pharmacology and Physiology of Brown Adipose Tissue in Human Disease and Treatment
Larson, C. J. (2018) · Handbook of experimental pharmacology · doi:10.1007/164_2018_184 · Cited by 25 · see citing works
Innervation of Brown Adipose Tissue and its Role in Thermogenesis
Bartness, T. J. (2005) · Cited by 25 · see citing works
Arha, D., Ramakrishna, E., Gupta, A. P., Rai, A. K., Sharma, A., Ahmad, I., Riyazuddin, M., Gayen, J. R., Maurya, R., & Tamrakar, A. K. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.07.015 · Cited by 25 · see citing works
ATP-Sensitive Potassium Channel-Deficient Mice Show Hyperphagia but Are Resistant to Obesity
Park, Y.-B., Choi, Y.-J., Park, S. Y., Kim, J. Y., Kim, S. H., Song, D., Won, K., & Kim, Y. W. (2011) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2011.35.3.219 · Cited by 24 · see citing works
“2 KO mice (data not shown), suggesting a lower fuel efficiency during exercise, which may result in the lean phenotype by magnifying the benefit of activity [28].”
Adipose targets for obesity drug development
Boss, O., & Bergenhem, N. C. H. (2006) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.10.1.119 · Cited by 12 · see citing works
“•• An original article showing induction of brown-like adipocytes rich in mitochondria, but devoid of UCP1, by a β3-AR agonist.”
BackgroundInfluentialKATP channels process nucleotide signals in muscle thermogenic response
Reyes, S., Park, S., Terzic, A., & Alekseev, A. (2010) · Critical reviews in biochemistry and molecular biology · doi:10.3109/10409238.2010.513374 · Cited by 11 · see citing works
“processes to maintain the whole spectrum of cellular and core body functions concomitantly producing heat, that is, in thermogenesis (Else et al., 2004; Himms-Hagen, 2004; Levine, 2007).”
BackgroundHomeostatic non-shivering thermogenesis in humans facts and hypotheses
Сонькин, В. Д., Kirdin, A. A., Андреев, Р. С., & Akimov, E. B. (2010) · Human Physiology · doi:10.1134/s0362119710050129 · Cited by 10 · see citing works
“through white to brown adipocytes con version in some authors’ view [26, 33].”
BackgroundResultAverting Comfortable Lifestyle Crises
Bilton, R. F. (2013) · Science Progress · doi:10.3184/003685013x13743292107915 · Cited by 10 · see citing works
Adiposity and the Gut - The Role of Gut Hormones
Amber, V., & Bloom, S. R. (2007) · Current Nutrition & Food Science · doi:10.2174/1573401310703010075 · Cited by 3 · see citing works
Li, Z., Wang, T., Fu, Y., Chen, F., & Li, S. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1732329 · Cited by 1 · see citing works
“The term “ Exercise mimetics ” was fi rst proposed by Himmis-Hagen in 2004 (25), and MOTS-c was discovered by Lee in 2015 (6).”
Adipose Tissue and Skeletal Muscle Plasticity in Obesity and Metabolic Disease
Ukropec, J., & Ukropcov, B. (2012) · InTech eBooks · doi:10.5772/28506
“Generation of “exercise pill” targeting organ systems involved in facultative thermogenesis had been envisaged (Himms-Hagen 2004).”
BackgroundGosselin, C. (2012) · uO Research (University of Ottawa) · doi:10.20381/ruor-5130
“Possibility arise that Ca2+cycling could be stimulated in the cold © Chantal Gosselin, Ottawa, Canada, 2012 7 through circulating NA and cAMP-dependent mechanisms (Himms-Hagen 2004), since they are responsible for the activation of TD2 through β-receptors (Hosoi et al. 1999).”
BackgroundInfluentialAdipose Drug Targets for Obesity Treatment
Giacobino, J., Lehr, L., & Boss, O. (2007) · CRC Press eBooks · doi:10.1201/9781420005479.pt4
Physiology, pathophysiology, and aging
Berlin, A. L. (2011) · CRC Press eBooks · doi:10.3109/9781841848792-5
Physiology, pathophysiology and aging
(2011) · CRC Press eBooks · doi:10.3109/9781841848792-3
Physiology, pathophysiology, and aging
Berlin, A. L. (2011) · Series in cosmetic and laser therapy · doi:10.3109/9781841848792.002
Availability of Journal Back Issues
(2005) · Journal of the American Academy of Dermatology · doi:10.1016/s0190-9622(05)02664-2
Herrera, C. L. (2015) · theses.fr (ABES) · doi:10.70675/d09d7e9cz079fz4faaz985aza9cd4fc18f18
“Furthermore, endurance exercise training (Himms-Hagen, 2004; Goodyear, 2008), or chronic cold exposure (Puigserver et al., 1998; Lin, 2002) may trigger a remodeling of muscular fibers, helping protect against obesity and related metabolic disorders.”
Background
- Authors
- Himms-Hagen, J.
- Venue
- Current Drug Target -CNS & Neurological Disorders
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2004-10-01
- Volume
- 3
- Issue
- 5
- Pages
- 389-409
- ISSN
- 1568-007X (ISSN-L)
- OpenAlex
- W2056349137
- Cited by
- 39
- References
- 0
- Citations by year
- 2026: 1 · 2022: 1 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 5 · 2013: 1 · 2012: 5
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- CNS & Neurological Disorders - Drug Targets (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- energy expenditure, thermogenesis, brown adipose tissue, skeletal muscle, muscle fiber type shift, starvation recovery, obesity, white adipose tissue browning, therapeutic target, metabolic plasticity
- MeSH terms
- Adaptation, Physiological, Animals, Adipose Tissue, Brown, Energy Metabolism, Humans, Obesity, Drug Design, Exercise, Muscle, Skeletal, Anti-Obesity Agents, Thermogenesis, Mice, Rats
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.
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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
