The tight coupling of thermoregulation to energy homeostasis allows body temperature and body weight to be defended, despite dramatic changes in ambient temperature. A central goal of this proposal is to clarify how adaptive changes in energy intake are coupled to changes in ambient temperature, with a focus on the hyperphagic response to cold exposure. Although untested, it has been an accepted view that cold-induced hyperphagia is initiated following the development of a negative energy state (i.e., a loss of body fat stores). However, our recent findings demonstrate that food intake and increases in heat production occur rapidly and in parallel following acute cold exposure, and likely precede the development of a negative energy state. Also, we find our recent findings implicate a role for agouti-related peptide (Agrp) neurons in the adaptive feeding response since increases of Agrp neuron activity precede and are required for cold-induced hyperphagia, but not cold-induced thermogenic responses. Here, we propose the novel and interrelated hypotheses that cold- induced activation of thermoregulatory circuits drive adaptive changes of both energy expenditure and food intake concurrently, that these responses occur independently of and serve to minimize changes in energy balance, and that they are uncoupled in obese animals, leading to weight loss. The overarching goal of the proposal is to identify and functionally characterize the neurocircuitry linking thermoregulation to control of Agrp neuronal activity and associated feeding responses. Studies proposed herein will, therefore, shed new light not only on how energy homeostasis and food intake are coupled to one another, but how this coupling process becomes disrupted in obese animals. Proposed studies seek 1) to characterize neurocircuits that link thermoregulation to Agrp neuron activation and cold-induced hyperphagia and 2) to determine how neuronal and circuit-level dysfunction occurs following the introduction of a high-fat diet. To accomplish this, we will use state-of-the-art neuroscience techniques including chemogenetics, optogenetics, and in vivo fiber photometry approaches are utilized, in combination with immunohistochemical and advanced metabolic phenotyping. Together, this work will advance the understanding of the neurocircuitry linking thermoregulation to Agrp neuronal activity and feeding and may identify novel strategies for the treatment of obesity.
Obesity and its associated complications are some of the most pressing and costly biomedical challenges confronting modern society. Our recent work suggests that aspects of obesity may be due to a disconnection between thermoregulation and food intake control in the brain. By functionally mapping and characterizing the connections made between thermoregulatory and food intake circuits, our proposed work has the potential to fundamentally advance our understanding of how the brain regulates feeding and identify targets for obesity treatment.
