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.
According to the U.S. Surgeon General, nearly 300,000 deaths per year are attributable to obesity and health care costs associated with obesity exceed $140 billion. A better understanding of both how the brain regulates energy balance and the impact of obesogenic diet on the circuits that control body weight and appetite is needed to develop effective therapeutic approaches to prevent and treat obesity. This study will determine how calorie-dense diets remodel the activity of the neurons that regulate appetite and body weight.
|El Ayachi, Ikbale; Zhang, Jun; Zou, Xiao-Ying et al. (2018) Human dental stem cell derived transgene-free iPSCs generate functional neurons via embryoid body-mediated and direct induction methods. J Tissue Eng Regen Med 12:e1836-e1851|
|Wei, Wei; Pham, Kevin; Gammons, Jesse W et al. (2015) Diet composition, not calorie intake, rapidly alters intrinsic excitability of hypothalamic AgRP/NPY neurons in mice. Sci Rep 5:16810|
|Neuner, Sarah M; Wilmott, Lynda A; Hope, Kevin A et al. (2015) TRPC3 channels critically regulate hippocampal excitability and contextual fear memory. Behav Brain Res 281:69-77|
|Baver, Scott B; Hope, Kevin; Guyot, Shannon et al. (2014) Leptin modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus. J Neurosci 34:5486-96|