Is the Energy Homeostasis System Inherently Biased Toward Weight Gain?

Michael W. Schwartz, Stephen C. Woods, Randy J. Seeley, Gregory S. Barsh, Denis G. Baskin, Rudolph L. Leibel

Disclosures

Diabetes. 2003;52(2) 

In This Article

Discussion

The model proposed here is not intended to explain how obesity occurs. Rather, the intent is to better understand the apparent bias of the energy homeostasis system in favor of weight gain. This information is important for the development of an interpretive and experimental framework that encompasses genetic and environmental factors related to obesity. Clarifying the regulation of neuronal pathways by adiposity signals and their contribution to adaptive responses to weight loss and weight gain is critical if we are to understand how mammalian systems evolved to defend against the threat of starvation. This evolutionary process may have involved selection of allelic variants of the genes discussed, as well as others that predispose to weight gain.

From a clinical perspective, there is a compelling need to understand how weight gain occurs so readily in the context of a homeostatic system that regulates body fat. Such understanding will assist in the selection of appropriate drug targets and will facilitate therapeutic decision-making in a future where multiple drug options for obesity treatment are likely to exist. For example, inhibition of anabolic activity is unlikely to cause weight loss by itself if anabolic pathways are already hypoactive under ad libitum feeding conditions, but it may help to maintain weight loss induced by other interventions (since weight loss should activate anabolic effectors that had previously been quiescent). Conversely, the weight-reducing efficacy of drugs that activate catabolic effector pathways (e.g., agonists of melanocortin receptors) are likely to be potentiated by concomitant inhibition of anabolic pathways that will otherwise be activated as body fat is lost. Drug combinations that both activate catabolic and inhibit anabolic pathways, or alternatively, act downstream of these neuronal systems, may ultimately be required for optimal pharmacotherapy of obesity.

The means by which our bodies strive to defend fat stores in the face of large variation in day-to-day energy intake and expenditure is an area of fundamental biomedical importance. The ability to improve the lives of individuals with disorders of this process will require a detailed understanding of how this system works. While the rapid pace at which new signaling molecules are being discovered continues to generate intense research interest, valid physiological models with which to interpret experimental and clinical phenomena are essential for the development of more effective therapeutic strategies.

Footnotes

-MSH, -melanocyte stimulating hormone; AgRP, agouti-related protein; ARC, arcuate nucleus; BBB, blood-brain barrier; CART, cocaine-amphetamine-regulated transcript; LHA, lateral hypothalamic area; MCH, melanin concentrating hormone; Mc4r, melanocortin-4 receptor; NPY, neuropeptide Y; PI 3-kinase, phosphatidylinositol 3-kinase; POMC, prepro-opiomelanocortin.

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