title: Distinct networks of leptin- and insulin-sensing neurons regulate thermogenic responses to nutritional and cold challenges.
abstract: Defense of core body temperature (Tc) can be energetically costly; thus, it is critical that thermoregulatory circuits are modulated by signals of energy availability. Hypothalamic leptin and insulin signals relay information about energy status and are reported to promote thermogenesis, raising the possibility that they interact to direct an appropriate response to nutritional and thermal challenges. To test this idea, we used an Nkx2.1-Cre driver to generate conditional knockouts (KOs) in mice of leptin receptor (L(2.1)KO), insulin receptor (I(2.1)KO), and double KOs of both receptors (D(2.1)KO). L(2.1)KOs are hyperphagic and obese, whereas I(2.1)KOs are similar to controls. D(2.1)KOs exhibit higher body weight and adiposity than L(2.1)KOs, solely due to reduced energy expenditure. At 20-22°C, fed L(2.1)KOs maintain a lower baseline Tc than controls, which is further decreased in D(2.1)KOs. After an overnight fast, some L(2.1)KOs dramatically suppress energy expenditure and enter a torpor-like state; this behavior is markedly enhanced in D(2.1)KOs. When fasted mice are exposed to 4°C, L(2.1)KOs and D(2.1)KOs both mount a robust thermogenic response and rapidly increase Tc. These observations support the idea that neuronal populations that integrate information about energy stores to regulate the defense of Tc set points are distinct from those required to respond to a cold challenge.
authors.affiliation: Institute of Human Nutrition, Columbia University, New York, NY Naomi Berrie Diabetes Center, Columbia University, New York, NY.
authors.forename: Angie C N
authors.initials: AC
authors.lastname: Chong
authors.affiliation: Naomi Berrie Diabetes Center, Columbia University, New York, NY.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Greendyk
authors.affiliation: Naomi Berrie Diabetes Center, Columbia University, New York, NY Department of Pathology and Cell Biology, Columbia University, New York, NY lz146@cumc.columbia.edu.
authors.forename: Lori M
authors.initials: LM
authors.lastname: Zeltser
mesh_terms: D050154:Adiposity / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001833:Body Temperature Regulation / Q000502:physiology*; D002151:Calorimetry; D003080:Cold Temperature; D004435:Eating / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D005215:Fasting / Q000502:physiology; D005260:Female; D005280:Fenoterol; D054439:Ghrelin / Q000097:blood; D007328:Insulin / Q000097:blood*; D020738:Leptin / Q000097:blood*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D054439:Ghrelin; D007328:Insulin; D020738:Leptin; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D054411:Receptors, Leptin; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; C515447:leptin receptor, mouse; D005280:Fenoterol; D011972:Receptor, Insulin