Jonathan Roth

Abstract
“Weighing in on Synergy”: Neurohormonal Combinations for Obesity

The complex, integrated, neurohormonal regulation of body weight is characterized by considerable redundancy of feeding pathways and potent counter-regulatory responses. One approach to obesity drug development, therefore, is to combine peripheral hormones that target multiple sites of action to prevent or minimize metabolic counter-regulatory adaptations triggered by weight loss. The combined administration of the pancreatic b-cell hormone amylin (a short-term satiety signal) with the adipokine leptin (a long-term adiposity signal) highlights the value of this approach. In obese, leptin-resistant rats, amylin/leptin treatment elicited synergistic effects on body weight and markedly reduced adiposity, yet prevented the decline in energy expenditure and shift toward carbohydrate utilization that is evoked by caloric restriction. The central mechanisms of amylin/leptin synergy include the activation of complementary neuronal signaling pathways, with amylin “priming” the hypothalamus to respond to leptin. For example, amylin amplified low-dose leptin signaling in lean rats, whereas in amylin knock-out mice, central leptin signaling was diminished. Sustained amylin treatment increased hypothalamic leptin binding, and in the obese state restored hypothalamic leptin activation. Importantly, clinical evidence to support the concept of an integrated neurohormonal therapy for obesity was recently obtained in overweight/obese humans where combination treatment with the amylin analog pramlintide and the leptin analog metreleptin elicited greater weight loss than did either agent alone. The current presentation will highlight these and other findings from our translational research program aimed at elucidating the interaction between islet-, gut-, and adipocyte-derived hormonal signals.

Keywords: synergy, amylin, leptin, combination

Biography

Jonathan D. Roth has studied the behavioral and pharmacological effects of peptide and small molecule combination-based obesity therapeutics in non-clinical models for the past 15 years. He received his Ph.D. from the University of Florida (1999; “Combined Drug Treatment For Obesity”). After a post-doctoral fellowship at the University of Pennsylvania (1999-2002), he joined Immusol, Inc. and examined the potential of gene knockdown techniques to inhibit adipocyte differentiation. He is currently a Senior Investigator at Amylin Pharmaceuticals, Inc. contributing to a translational research program aimed at identifying naturally occurring neurohormonal synergies for the development of combination therapies.