Leptin and the New Biology of Obesity

Yesterday, I co-chaired and spoke at a session on obesity management at the 25th Annual Scientific Meeting of the American Society of Hypertension in New York.

Later in the afternoon, Jeff Friedman, who played a prominent role in the discovery of leptin, thereby hearkening in the modern era of adipocyte and appetite physiology, presented an update on the potential role of this system in the therapeutic management of obesity and diabetes.

While leptin has therapeutic efficacy in rare cases of genetic leptin deficiency, its use in non-genetic “garden-variety” obesity has proven disappointing. Indeed, there appears to be more evidence that leptin plays an important role in defending against weight loss, than to support its roled in the prevention of weight gain.

Thus, the dramatic decline in sympathetic activity, fall in metabolic rate and increased hunger that follows weight loss is likely due to the decrease in the leptin signal that unleashes the biological drive to rapidly regain weight and defend against further weight loss.

Indeed in most obese individuals, leptin levels increase in proportion to weight gain, while at the same time these individuals display leptin resistance, rendering these increased levels of leptin as biologically ineffective (a notion akin to the hyperinsulinemia associated with insulin resistance in patients with type 2 diabetes mellitus).

This state of affairs limits the use of leptin for the treatment of obesity, as the high doses of leptin that would be required to overcome the leptin resistance are poorly tolerated.

But recent research points to another possible use of leptin (or leptin analogues) in weight management, namely as a way to prevent weight regain after weight loss.

The basic idea here is to substitute leptin after weight loss in an attempt to trick the body into thinking that it still has as much body fat as it had before. Studies that have combined the peptide pramlinitide (which induces weight loss) with metreleptin (a long-acting analogue of leptin) are showing promise in terms of long-term weight loss maintenance (albeit at the cost of injections).

Friedman also discussed new data showing that leptin may have potent antidiabetogenic effects independent of any effects on weight loss or food intake. Some of this action may be mediated by leptin’s ability to increase plasma levels of Insulin-like Growth Factor Binding Protein 2 (IGFBP2), which has profound inhibitory effects on hepatic glucose output.

Several studies to further exploring the interaction between leptin and IGFBP2 and the antidiabetic effect of this protein are currently underway in Freidman’s lab to better understand these novel findings.

New York, New York

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Hedbacker K, Birsoy K, Wysocki RW, Asilmaz E, Ahima RS, Farooqi IS, & Friedman JM (2010). Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell metabolism, 11 (1), 11-22 PMID: 20074524