157-OR: High-Fat–Diet Feeding Disrupts Thermal Responsiveness of AgRP Neurons

Abstract

To defend energy homeostasis in the cold requires energy expenditure (to support thermogenesis) and energy intake increase, enabling core temperature to be maintained with no change to body fat stores. When acutely housed at a mild cold (14°C) , mice increase both food intake and heat production rapidly (∼minutes) , and these responses occur in parallel. We hypothesized a role for Agouti-related peptide (AgRP) neurons in this response and find their activity is regulated by thermal sensory input, and they increase activity, measured by Fos induction and fiber photometry, upon cold sensation, and reduce activity as sensed temperatures rise. By inhibiting AgRP neurons during acute cold exposure, we also find this increase in AgRP neuron activity is required for the hyperphagic response to cold. Recent evidence found high-fat diet (HFD) feeding reduced AgRP neuron responsiveness to gastric hormones and standard chow diet presentation, and we hypothesized that their response to thermal input might also be blunted. We find that although 12-week HFD-fed mice exhibit intact thermogenic responses to cold and defend a normal core body temperature, they fail to increase energy intake and consequently experience weight loss not observed in chow-fed controls. This uncoupling of energy intake from energy expenditure is present even after a shorter, 2-week exposure to HFD-feeding, implying a role for diet separate from obesity in the phenotype. Using Agrp-Cre/GFP marker mice, we find acute cold exposure rapidly induces Fos in chow-fed mice, but this response is lacking in HFD-fed mice. This effect correlates with a failure to increase hypothalamic Agrp mRNA even after five days of mild cold exposure. Using photometry to measure AgRP neuron calcium activity, we find activity changes associated with thermal input, both cold and warm, are blunted with HFD feeding. Further testing will determine exactly how the food intake response to cold has become uncoupled from other thermoregulatory responses across the development of obesity. Disclosure J.D.Deem: None. T.P.Doan: None. B.N.Phan: None. K.Ogimoto: None. S.J.W.Hu: None. B.Wu: None. M.W.Schwartz: None. G.J.Morton: Research Support; Novo Nordisk A/S. Funding American Diabetes Association (1-19-PDF-103) ; NIDDK (K01 DK126793) , NIDDK (DK089056) , NIDDK (DK124238) , NIDDK (DK035816) , NIDA (P30 DA048736) , NIDDK (DK035816) , NIDDK (DK17047)