Modulation of AgRP Neuronal Excitability: Role of Diet and Body Weight

Jackson Laboratory, Bar Harbor ME

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Abstract

DESCRIPTION (provided by applicant): The prevalence of obesity in the United States has steadily increased in recent years, along with the associated comorbidities, such as hypertension, type 2 diabetes, heart disease, stroke, and some cancers. In humans, obesity is largely a consequence of poor diet and lifestyle, particularly excess caloric intake. While appetite is a complex behavior, control of food intake begins in the brain, specifically in the arcuate nucleus of the hypothalamus, where a small group of neurons expressing Agouti-related Peptide (AgRP) act as internal sensory neurons that translate peripheral and synaptic signals of metabolism and energy balance. Increased activity of AgRP neurons is associated with increased food intake, and it is evident that dysfunction in these neurons and the downstream circuits is a significant contributor to the development and maintenance of obesity. We have shown that chronic consumption of a high-fat, calorie dense diet results in electrical remodeling of AgRP neurons, resulting in persistently increased activity. The hypothesis driving this this proposal is that a high-fat diet induces changes in the expression, function, and localization of the the ion channels that determine the intrinsic excitability of AgRP neurons, resulting in increased neuronal output. We will test this hypothesis by 1) characterizing the impact of a high-fat diet on the localization and function of the voltage-gated Ca2+ and K+ channels that regulate AgRP neuronal excitability, 2) investigate the modulation of these channels by peripheral and synaptic energy balance signals, and 3) to determine the time course of diet- induced changes in AgRP neuronal function and the role of diet composition in this process. The consequence of an obesogenic diet on AgRP neuronal activity will be determined using whole-cell current- and voltage-clamp in brain slices prepared from mice fed either a low-fat or high-fat diet to mimic the human disease. The results of this proposal will shed light on the mechanisms that govern excitability in AgRP neurons and the impact of diet on these mechanisms. The ion channel proteins that underlie this process may represent novel therapeutic targets.