title: Leptin action in the dorsomedial hypothalamus increases sympathetic tone to brown adipose tissue in spite of systemic leptin resistance.
abstract: Leptin regulates body weight in mice by decreasing appetite and increasing sympathetic nerve activity (SNA), which increases energy expenditure in interscapular brown adipose tissue (iBAT). Diet-induced obese mice (DIO) are resistant to the anorectic actions of leptin. We evaluated whether leptin still stimulated sympathetic outflow in DIO mice. We measured iBAT temperature as a marker of SNA. We found that obese hyperleptinemic mice have higher iBAT temperature than mice on regular diet. Conversely, obese leptin-deficient ob/ob mice have lower iBAT temperature. Additionally, leptin increased SNA in obese (DIO and ob/ob) and control mice, despite DIO mice being resistant to anorectic action of leptin. We demonstrated that neurons in the dorsomedial hypothalamus (DMH) of DIO mice mediate the thermogenic responses to hyperleptinemia in obese mammals because blockade of leptin receptors in the DMH prevented the thermogenic effects of leptin. Peripheral Melotan II (MTII) injection increased iBAT temperature, but it was blunted by blockade of DMH melanocortin receptors (MC4Rs) by injecting agouti-related peptide (AgRP) directly into the DMH, suggesting a physiological role of the DMH on temperature regulation in animals with normal body weight. Nevertheless, obese mice without a functional melanocortin system (MC4R KO mice) have an increased sympathetic outflow to iBAT compared with their littermates, suggesting that higher leptin levels drive sympathoexcitation to iBAT by a melanocortin-independent pathway. Because the sympathetic nervous system contributes in regulating blood pressure, heart rate, and hepatic glucose production, selective leptin resistance may be a crucial mechanism linking adiposity and metabolic syndrome.
authors.affiliation: Department of Physiology, Faculty of Medicine, Monash University and Monash Obesity and Diabetes Institute, Melbourne, Victoria 3800, Australia. pablo.enriori@monash.edu
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Enriori
authors.forename: Puspha
authors.initials: P
authors.lastname: Sinnayah
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Simonds
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garcia Rudaz
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cowley
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004302:Dorsomedial Hypothalamic Nucleus / Q000187:drug effects / Q000502:physiology*; D004351:Drug Resistance / Q000187:drug effects / Q000502:physiology; D020738:Leptin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors / Q000502:physiology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*; D022722:Thermogenesis / Q000187:drug effects / Q000502:physiology*
chemical_list: D020738:Leptin; D054411:Receptors, Leptin