Review
Insights into amylin–leptin synergy

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Although the adipokine leptin is regarded as the prototypical long-term signal of energy balance, obese individuals are largely nonresponsive to exogenous leptin administration. Restoration of leptin responsiveness in obesity has been elusive despite a detailed understanding of the molecular mechanisms of leptin signaling. Recent translational research findings point to a potential therapeutic approach that incorporates amylin (a β-cell hormone) and leptin agonism, with amylin restoring or enhancing leptin sensitivity. Here we hypothesize various physiological, neurobiological and molecular mechanisms that could mediate the interaction of these two neurohormonal signals and discuss several methodological challenges. Understanding how amylin agonism improves leptin function could point to general therapeutic strategies for combating leptin resistance and associated obesity.

Section snippets

Leptin ‘resistance’ in obesity

Body weight homeostasis is a multi-factorial dynamic process that requires the central integration of peripheral signals of energy stores with physiological or behavioral responses 1, 2, 3. In general, these peripheral signals include gastric peptides (cholecystokinin, peptide YY, ghrelin, bombesin) that act as short-term regulators of satiation and feeding behavior, and longer-term signals of energy balance such as insulin. Recently, adipose tissue has emerged as an active endocrine organ that

Leptin ‘sensitivity’ in obesity

Although there are gaps in our understanding of the temporal relationship between hyperleptinemia, leptin resistance and the development or maintenance of obesity, clearly a reduction in plasma leptin (experienced during states of prolonged underfeeding or starvation) is a relevant and potent physiological signal related to energy balance regulation, rather than increased leptin in states of weight gain [28]. The ‘leptin sensitivity threshold’ concept proposed by Leibel contends that an

Amylin acts synergistically with leptin to reduce body weight in obesity

Amylin is secreted from pancreatic β-cells in proportion to insulin and has multiple physiological roles, notably as a satiogenic signal, an inhibitor of gastric emptying and a glucoregulatory molecule. The physiological effects of peripheral amylin are almost solely mediated via interaction with its receptor in the area postrema (AP) of the brain stem [30]. Areas downstream of the AP, including the nucleus of the solitary tract (NTS), the lateral parabrachial nucleus and the central nucleus of

Is there a ‘sweet spot’ for synergy?

Recent clinical findings established clear proof-of-concept for combined amylin and leptin agonism leading to greater weight loss than either treatment alone. First, in a 24-week randomized, double-blind clinical proof-of-concept study in overweight or obese subjects (BMI 27–35 kg/m2) following 4 weeks of pre-treatment with pramlintide (an amylin agonist), co-administration of methionyl recombinant human leptin (metreleptin) and pramlintide elicited significant weight loss of ∼13% compared with

Hypothalamic and extra-hypothalamic regions

Although the pharmacology of amylin and leptin in different degrees of leptin resistance deserves further investigation, neurobiological mechanistic studies mapping circuits of activated neurons in lean, obese and amylin knockout animals have revealed several notable cooperative central interactions. In brief, in lean rats, acute central leptin increased the food-intake-inhibitory effects of peripherally administered amylin [37]. There are also several lines of evidence supporting a critical

Neurobiological studies

Clearly, further neurobiological studies into the mechanisms and neural pathways recruited by amylin–leptin are warranted. Clarification of the phenotype and projection fields of neurons in which amylin restores or enhances leptin signaling could yield important insights into critical regions involved in overcoming leptin resistance. The VMH has emerged as a consistent candidate region in several of our studies 34, 41 and VMH signals such as histamine play an important role in the individual

Summary

Exogenous pharmacological amylin synergizes with leptin to induce marked and sustained fat-specific body weight loss in DIO rats. Clinical weight loss studies with combined pramlintide and metreleptin agonism confirm an interaction between these two signaling systems and have identified sub-populations (encompassing a majority of overweight or obese patients) that might be particularly responsive. Although there are limitations in terms of the availability and applicability of extant molecular

Disclosure statement

J.L.T., D.G.P. and J.D.R. are employed by and own stock in Amylin Pharmaceuticals, Inc.

Acknowledgements

The authors gratefully acknowledge Mary Erickson and Jean Chan for helpful comments and discussion during preparation of this review.

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