ABSTRACT
Adiponectin can act in the brain to increase energy expenditure and reduce body weight by mechanisms not entirely understood. We found that adiponectin type 1 and type 2 receptors (AdipoR1 and AdipoR2) are expressed in warm sensitive neurons of the hypothalamic preoptic area (POA) which play a critical role in the regulation of core body temperature (CBT) and energy balance. Thus, we tested the ability of adiponectin to influence CBT in wild-type mice and in mice deficient for AdipoR1 or AdipoR2. Local injection of adiponectin into the POA induced prolonged elevation of core body temperature and decreased respiratory exchange ratio (RER) indicating that increased energy expenditure is associated with increased oxidation of fat over carbohydrates. In AdipoR1 deficient mice, the ability of adiponectin to raise CBT was significantly blunted and its ability to decrease RER was completely lost. In AdipoR2 deficient mice, adiponectin had only diminished hyperthermic effects but reduced RER similarly to wild type mice. These results indicate that adiponectin can contribute to energy homeostasis by regulating CBT by direct actions on AdipoR1 and R2 in the POA.
Subject(s)
Adiponectin/pharmacology , Body Temperature/drug effects , Preoptic Area/cytology , Receptors, Adiponectin/metabolism , Sensory Receptor Cells/physiology , Analysis of Variance , Animals , Calorimetry, Indirect , Energy Metabolism/drug effects , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , In Vitro Techniques , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Adiponectin/deficiency , Sensory Receptor Cells/drug effects , Telemetry , Thermosensing/drug effects , Thermosensing/physiologyABSTRACT
OBJECTIVE: Temperature and nutrient homeostasis are two interdependent components of energy balance regulated by distinct sets of hypothalamic neurons. The objective is to examine the role of the metabolic signal insulin in the control of core body temperature (CBT). RESEARCH DESIGN AND METHODS: The effect of preoptic area administration of insulin on CBT in mice was measured by radiotelemetry and respiratory exchange ratio. In vivo 2-[(18)F]fluoro-2-deoxyglucose uptake into brown adipose tissue (BAT) was measured in rats after insulin treatment by positron emission tomography combined with X-ray computed tomography imaging. Insulin receptor-positive neurons were identified by retrograde tracing from the raphe pallidus. Insulin was locally applied on hypothalamic slices to determine the direct effects of insulin on intrinsically warm-sensitive neurons by inducing hyperpolarization and reducing firing rates. RESULTS: Injection of insulin into the preoptic area of the hypothalamus induced a specific and dose-dependent elevation of CBT mediated by stimulation of BAT thermogenesis as shown by imaging and respiratory ratio measurements. Retrograde tracing indicates that insulin receptor-expressing warm-sensitive neurons activate BAT through projection via the raphe pallidus. Insulin applied on hypothalamic slices acted directly on intrinsically warm-sensitive neurons by inducing hyperpolarization and reducing firing rates. The hyperthermic effects of insulin were blocked by pretreatment with antibodies to insulin or with a phosphatidylinositol 3-kinase inhibitor. CONCLUSIONS: Our findings demonstrate that insulin can directly modulate hypothalamic neurons that regulate thermogenesis and CBT and indicate that insulin plays an important role in coupling metabolism and thermoregulation at the level of anterior hypothalamus.
Subject(s)
Body Temperature/physiology , Hyperthermia, Induced/methods , Insulin/pharmacology , Neurons/physiology , Adipose Tissue, Brown/physiology , Animals , Body Temperature/drug effects , Hypothalamus/drug effects , Hypothalamus/physiology , Injections , Insulin/administration & dosage , Male , Mice , Mice, Inbred C57BL , Preoptic Area/drug effects , Preoptic Area/physiology , TelemetryABSTRACT
We have characterized a newly generated mouse model of obesity, a mouse strain deficient in all five previously described leptin receptor isoforms. These transgenic mice, named the db (333)/db (333) mice, were identified from an ENU mutagenesis screen and carry a point mutation in the seventh exon of the db gene encoding the leptin receptor, resulting in a premature stop codon (Y(333)Stop) and gene product that lacks STAT signaling domains. db (333)/db (333) mice have a morbidly obese phenotype, with body weights diverging from wild type as early as 4 weeks of age (P < 0.05). To determine the contribution of the short isoforms of the leptin receptor in this metabolic phenotype, we performed an extensive metabolic characterization of the db (333)/db (333) mouse in relation to the well-characterized db/db mouse lacking only the long form of the leptin receptor. db (333)/db (333) mice have similar endocrine and metabolic parameters as previously described in other leptin receptor transgenic mice including db/db mice that lack only the long isoform of the leptin receptor. However, db (333)/db (333) mice show a subtle trend toward higher body weight and insulin levels, lower oxygen, carbon dioxide production, respiratory exchange ratio (RER), and temperature than db/db mice suggesting the short isoforms may play an additional role in energy homeostasis.
