Document text
Principal Investigator: Li Ye
Organization: SCRIPPS RESEARCH INSTITUTE, THE
Fiscal Year: 2024
Award: $679,018
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary
Obesity is a major public health problem. Modulating energy expenditure through behavioral or
pharmacological intervention is a key strategy to alter energy balance and battle obesity and metabolic
diseases. Targeting molecular pathways underlying the cold-induced non-shivering thermogenesis has been
an important and promising strategy to elevate energy expenditure in animals and humans. However, it is well-
known that mammals compensatorily increase food intake due to higher expenditure, such as in the cold.
While it is generally agreed that the brain centrally controls this feedback, the neural mechanism underlying
this coupling is largely unknown. Here, we propose to systematically investigate the behavioral, metabolic, and
circuit basis of cold-induced feeding. By combining calorimetry and behavioral modeling, our preliminary study
demonstrated that cold-induced increase of food intake involves dynamic bi-directional behavioral switches
and is mediated by non-canonical feeding circuits. Using whole-brain clearing, lightsheet imaging, and c-fos
activity screening, we identified a group of nuclei at the ventral midline thalamus (vMT) associated with cold-
induced feeding. The central hypothesis is that the vMT nuclei are activated by the elevated energy
expenditure and recruit downstream targets to mediate cold-induced feeding. The first aim is to use in vivo
calcium imaging to measure the endogenous activity of vMT in relationship to cold and feeding behaviors. The
second aim is to use optogenetic and chemogenetic approaches to determine the causal significance of vMT
neural activity in driving cold-induced feeding. The third aim combines anatomical mapping and functional
manipulation to study how vMT integrates into the well-established feeding circuits in hypothalamic and limbic
systems. The completion of these studies will provide a new understanding of the coupling between energy
expenditure and intake in the brain, bringing many opportunities to leverage these mechanisms to maximize
and maintain the metabolic benefits from targeting energy expenditure.
Terms: <Acute><Adult-Onset Diabetes Mellitus><Affect><Agreement><Anatomic Sites><Anatomic structures><Anatomy><Animals><Assay><Automobile Driving><Autoregulation><Behavior><Behavioral><Behavioral Model><Bioassay><Biological Assay><Body Temperature><Brain><Brain Nervous System><Caloric Intake><Calorimetry><Causality><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Collaborations><Compensation><Costs and Benefits><Couples><Coupling><Data><Eating><Encephalon><Energy Expenditure><Energy Intake><Energy Metabolism><Esthesia><Etiology><Exercise><Expenditure><FOS gene><Fasting><Fats><Fatty acid glycerol esters><Feedback><Feeding behaviors><Fiber><Food><Food Intake><Foundations><Future><G0S7><Genetic><Goals><Heat Production><Homeostasis><Human><Hypothalamic structure><Hypothalamus><Image><In vivo two-photon calcium imaging><Ingestive Behavior><Intermediary Metabolism><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Ketosis-Resistant Diabetes Mellitus><Light><Limbic System><Mammalia><Mammals><Maps><Maturity-Onset Diabetes Mellitus><Measures><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolism><Midline Nuclear Group><Midline Nuclei of Thalamus><Midline Thalamic Nuclei><Modeling><Modern Man><Molecular Target><NIDDM><Natural Increases><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nucleus><Obesity><Output><Pathway interactions><Periventricular Nuclei of Thalamus><Photometry><Photoradiation><Physiologic><Physiological><Physiological Homeostasis><Protooncogene FOS><Public Health><Regulation><Research><Rewards><Rodent><Rodentia><Rodents Mammals><Role><Sensation><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><System><T2 DM><T2D><T2DM><Techniques><Thalamic structure><Thalamus><Thermogenesis><Thesaurismosis><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><adiposity><adult onset diabetes><biological signal transduction><c fos><c-fos Gene><c-fos Proto-Oncogenes><caloric dietary content><causation><corpulence><disease causation><driving><energy balance><fasted><fasts><feeding><feeding-related behaviors><gain of function><genetic approach><genetic strategy><hypothalamic><imaging><in vivo><in vivo calcium imaging><insight><interventional strategy><ketosis resistant diabetes><loss of function><maturity onset diabetes><metabolism disorder><neural><neural mechanism><neuromechanism><neuronal><nutrient intake activity><optogenetics><pathway><pharmacologic><recruit><screening><screenings><social role><thalamic><type 2 DM><type II DM><type two diabetes><v-FOS FBJ Murine Osteosarcoma Viral Oncogene Homolog>