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.