The Arcuate Nucleus: A Genetic Assessment of Function

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The brain detects alterations in diet and energy balance, and through various neural circuits, regulates energy intake and energy expenditure; Dysfunction of these homeostatic mechanisms results in obesity, an epidemic problem in affluent societies. Identification of the neural circuits, as well as the molecular effecters operating within these circuits, is a major focus of obesity research. The arcuate nucleus of the hypothalamus is hypothesized to play a major role in controlling body weight. Thus, it is critical that the key inputs to and outputs from this site be identified. Leptin, secreted by adipocytes, is thought to be an important afferent signal to the arcuate where it inhibits AGRP/NPY neurons and activates POMC neurons. Lipid is another, recently identified, potentially important afferent signal. It has been proposed that lipid metabolism within arcuate neurons, most likely AGRP/NPY neurons, serves as an important sensor for nutrient availability. Efferent signals from the arcuate include the neuropeptides, AGRP, NPY and alphaMSH. aMSH, released by POMC neurons, is the only efferent signal whose importance has been validated by genetic studies. Thus, it is likely that other important efferent signals also exist. These other important efferent signals could be classic, fast-acting neurotransmitters. AGRP/NPY neurons release GABA (inhibitory) while POMC neurons, for the most part, release glutamate (excitatory). Whereas glutamatergic and GABAergic signaling by arcuate neurons is likely to play a critical role in controlling body weight, this has not yet been evaluated. Thus, the goal of the present application is to use genetic tools (cre/lox neuron-specific gene manipulations) to test hypotheses that leptin signaling (Aim #1), "lipid sensing" (Aim #2) and neurotransmitter release (glutamate and GABA) by AGRP/NPY and POMC neurons, play important roles in preventing obesity. Novel discoveries of pathways within the arcuate nucleus that restrict body weight gain could identify new causes of obesity, as well as new therapies for this epidemic disease.