Gary J. Schwartz

Albert Einstein College of Medicine, USA

Abstract

[O06] Central nutrient sensing engages forebrain and hindbrain neuropeptide systems in the control of energy balance

Gary J. Schwartz, Clémence Blouet, Young-Hwan Jo and Xiaosong Li; Albert Einstein College of Medicine, USA

p70 S6 kinase 1 (S6K) is a major downstream effector of the mammalian target of rapamycin (mTOR), primarily implicated in the control of protein synthesis, cell growth and proliferation. Here we demonstrate that specific bidirectional molecular targeting of mediobasal hypothalamic (MBH) S6K activity in rats is sufficient to significantly alter food intake, body weight, hypothalamic orexigenic neuropeptide expression, hypothalamic leptin sensitivity and the metabolic and feeding responses to a fast. In addition, adenoviral-mediated constitutive activation of MBH S6K improved tolerance and protected against high-fat diet induced overeating, fat deposition and insulin resistance. Our results provide direct evidence that MBH S6K activity bidirectionally drives behavioral and metabolic determinants of energy balance, and promote its assessment as a therapeutic target in metabolic diseases.

In response to nutrient stimuli, the mediobasal hypothalamus (MBH) drives multiple neuroendocrine and behavioral mechanisms to regulate energy balance.  While central leucine reduces food intake and body weight, the specific neuroanatomical sites of leucine sensing, downstream neural substrates, and neurochemical effectors involved in this regulation remain largely unknown. Here we demonstrate that MBH leucine engages a neural energy regulatory circuit by stimulating POMC neurons of the MBH, oxytocin neurons of the paraventricular hypothalamus, and neurons within the brainstem nucleus of the solitary tract to acutely suppress food intake by reducing meal size. We identify central p70 S6 kinase and Erk1/2 pathways as intracellular effectors required for this response. Activation of endogenous leucine intracellular metabolism produced longer-term reductions in meal number. Our data identify a novel, specific hypothalamus– brainstem circuit that links amino acid availability and nutrient sensing to the control of food intake

Keywords:  S6K, mTOR, nutrient sensing, hypothalamus, obesity

Biography

Gary J. Schwartz, Ph.D., is a Professor of Medicine and Neuroscience at the Albert Einstein College of Medicine of Yeshiva University.  His basic research focuses on the neurobiology of feeding behavior, energy balance, and glucose homeostasis in obesity and diabetes.  He has published extensively on the role of gut-brain communication in the control of food intake and metabolism, and is a member of the editorial board of several related journals, including the American Journal of Physiology, Physiology and Behavior, and Endocrinology.  He is a senior member and Core leader for the Albert Einstein Diabetes Research and Training Center and the New York Obesity Research Center, and is the Director of the Skirball Institute for Nutrient Sensing.