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It Takes Two to Tango
  1. Jean L. Chan, MD,
  2. Jonathan D. Roth, PhD,
  3. Christian Weyer, MD
  1. From the Amylin Pharmaceuticals, Inc, San Diego, CA.
  1. Received May 15, 2009.
  2. Accepted for publication June 24, 2009.
  3. Reprints: Christian Weyer, MD, Amylin Pharmaceuticals, Inc, 9360 Towne Centre Dr, San Diego, CA 92121. E-mail: cweyer{at}amylin.com.
  4. The authors did not receive funding for this work from any of the following organizations: National Institutes of Health, Wellcome Trust, and Howard Hughes Medical Institute.
  5. Conflict of interest statement: J.L. Chan, J.D. Roth, and C. Weyer are employees of and stockholders in Amylin Pharmaceuticals, Inc.
  6. This symposium was supported in part by a grant from the National Center for Research Resources (R13 RR023236).

Combined Amylin/Leptin Agonism as a Potential Approach to Obesity Drug Development

Abstract

The discovery of leptin in 1994 was a seminal event in obesity research. It helped to establish that body weight is tightly regulated by a complex neurohormonal feedback system and that obesity should be viewed as a disorder with a strong biological basis rather than simply the result of poor lifestyle choices and lack of willpower.

Leptin, secreted from adipocytes, acts as a prototypic long-term (tonic) adiposity signal. Although nonclinical and clinical studies have provided unequivocal evidence that leptin plays a unique, pivotal role in body weight regulation, efforts to develop recombinant leptin (metreleptin) as a monotherapy for obesity have proven unsuccessful. Amylin, secreted from pancreatic β-cells, fulfills the criteria for a short-term (episodic) satiety signal. The amylin analog pramlintide elicits sustained reductions in food intake and body weight in obese rodents and humans.

A translational research program aimed at elucidating the interaction between different islet-, gut-, and adipocyte-derived hormones led to the discovery that combined amylin/leptin agonism induces marked, synergistic, fat-specific weight loss in leptin-resistant diet-induced obese rodents. In obese humans, combination treatment with pramlintide/metreleptin led to an approximately 13% weight loss after 24 weeks, significantly more than after treatment with pramlintide or metreleptin alone.

Collectively, these findings suggest that combined amylin/leptin agonism may have therapeutic utility as part of an integrated, neurohormonal approach to obesity pharmacotherapy.

Key Words
  • weight loss
  • pharmacotherapy
  • adiposity signal
  • satiety signal

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