Insulin Causes Hyperthermia by Direct Inhibition of Warm-Sensitive Neurons

Abstract

OBJECTIVETemperature 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 METHODSThe effect of preoptic area administration of insulin on CBT in mice was measured by radiotelemetry and respiratory exchange ratio. In vivo 2-[18F]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.RESULTSInjection 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.CONCLUSIONSOur 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.

Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies

“…Central injection of insulin into the PO/AH of the hypothalamus induced a dose-dependent increase in BAT thermogenesis and fatty acid oxidation in mice ( 80 ). Insulin is known to inhibit NPY/AgRP neurons and to stimulate POMC neurons ( 80 ). As these neurons are also involved in mediating BAT activity and thermogenesis (as described above), the effect of insulin on BAT thermogenesis is likely mediated by either increased MC4R activation or decreased NPY activation.…”

“…Central injection of insulin into the PO/AH of the hypothalamus induced a dose-dependent increase in BAT thermogenesis and fatty acid oxidation in mice ( 80 ). Insulin is known to inhibit NPY/AgRP neurons and to stimulate POMC neurons ( 80 ).…”

Adipose tissue in control of metabolism

“…In addition, several circulating factors such as insulin, leptin and GLP-1 have been identified to promote thermogenesis through targeting hypothalamus neurons and regulating activity of SNS (Shimizu et al 1987, Rahmouni & Morgan 2007, Sanchez-Alavez et al 2010, Harlan et al 2011, Lockie et al 2012, Beiroa et al 2014, Dodd et al 2015 (Fig. 3).…”

Central circuitries for body temperature regulation and fever

“…Projection of warm-sensitive neurons outside of the POA remains to be investigated. Suggesting a role of warmsensitive POA neurons in metabolic regulation, a recent study reported that a direct action of insulin on warm-sensitive POA neurons reduces their firing rates, and injection of insulin into the POA elicits a rise in body core temperature involving BAT thermogenesis (144).…”