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With the rising prevalence of obesity and insulin resistance syndrome, the need for understanding how humans regulate body weight has grown considerably. The interaction between peripheral signals of energy status from the gut or adipose tissue with neural signals in order to maintain energy homeostasis is enormously complex. Here we have described several, but by no means all, of the molecules involved in this process and how we think they function. Clearly some of these molecules, such as insulin and leptin, are extremely important for normal human health whereas the roles of others may be less critical although still important. For instance, despite the significant role of leptin in physiology, only a handful of obese people have been reported to have defective leptin signaling. So despite its key role as an adipokine leptin, it is unlikely to be the major cause of common human obesity. As insulin resistance syndrome and obesity are likely to be polygenic disorders, it is possible that still more molecules await discovery. The more important task for the future, perhaps, will be to decipher the underlying interactions between all of these signals in order to form a clear picture of the neuroendocrine regulation of food intake.

The ectopic fat theory has gained a significant body of supporting experimental data in the last few years. Yet, much investigational work remains to be done to precisely elucidate the mechanisms by which ectopic fat produce the downstream abnormalities of insulin resistance, hyperglycemia, atherogenic dyslipidemia, and hypertension observed in the metabolic syndrome. Such knowledge is needed not just to further validate the ectopic fat theory, but also to facilitate the design of pharmacological agents that specifically target the pathophysiology of the metabolic syndrome. This is particularly critical because currently there is no commercially available pharmacological treatment that completely reverses the metabolic syndrome, and physicians must rely on multiple drugs to individually treat the multiple abnormalities seen in the metabolic syndrome, i.e., dyslipidemia, hypertension, and insulin resistance. As a result, a significant proportion of the adult population with metabolic syndrome must currently rely on polypharmacy for treatment. In principle, it could be proposed that nonpharmacological treatment by means of weight loss and physical activity is all that is needed to contain the epidemics of obesity and the metabolic syndrome. However, on pragmatic terms, given the formidable challenges of attaining and then sustaining weight loss, there is a need for effective adjunctive pharmacological treatments for obesity and obesity-related insulin resistance.

Determining body mass index and waist circumference are the first steps in evaluating the risk to an individual patient. This can be complemented by more sophisticated methods and supplemented with laboratory data. If no specific etiologies are identified as contributory, and which could be ameliorated, then treatment can be designed, taking into considerations the patients needs and the realities of obesity. It is the role of the physician to evaluate individual patients and to estimate their health risk from obesity and aberrant fat deposition. As treatment approaches become more sophisticated and more effective, a proactive approach to risk assessment is an imperative.