Insulin Causes Hyperthermia by Direct Inhibition of Warm-Sensitive Neurons

The Harold L. Dorris Neurological Research Institute, Department of Molecular and Integrative Neurosciences, The Scripps Research Institute, La Jolla, California, USA.
Diabetes (Impact Factor: 8.1). 10/2009; 59(1):43-50. DOI: 10.2337/db09-1128
Source: PubMed


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).
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.
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.
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.

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    • "Second, the significant negative correlation of the HbA 1c with the core body temperature (a function of body metabolism) was obtained through non-invasive measurement at the inner canthus of the eye (Cronholm and Orlove, 2012; Ring et al., 2010) and at the tympanic region of the ear (Kiyatkin, 2011; Chan et al., 2004). This dependence of type 2 diabetes and its complications with alterations in the body metabolism was proven to be an early and vital health indicator (Maura-Neto et al., 2012; Sanchez-Alavez et al., 2010). Third, the sluggishness of the bio-chemically measured HbA 1c in the diagnosis of the type 2 diabetes and the pre-diabetes was revealed in comparison with the IR thermography. "
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    • "Indirect calorimetry was performed as previously described (Sanchez-Alavez et al., 2010) using the Comprehensive Lab Animal Monitoring System (CLAMS; Columbus Instruments, Columbus , OH, USA) on acclimated (for 2–3 days), singly housed mice using a computer-controlled, open-circuit system (Oxymax System , Columbus Instruments, Columbus, OH, USA). RER was calculated as VCO 2 /VO 2 . "
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