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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    ABSTRACT: The present study aims to estimate and validate the glycated haemoglobin (HbA(1c)) using non-contact infrared thermography. The diagnostic threshold was set as (HbA(1c)⩾48 mmol/mol). The optimal regression model [r=0.643, p=0.000] was achieved from the significant variables correlating with the HbA(1c) and the validation was performed against the bio-chemical assay to indicate the sensitivity, specificity, positive predictive value, negative predictive value and with an accuracy of [90%, 55%, 65%, 85% and 72%] respectively. The non-invasive core body temperature measurement at the inner canthi of eye [r=-0.462, p<0.01] indicated negative correlation with HbA(1c), that signifies the early metabolic changes. In type 2 diabetes, the core body temperature decreases with a decrease in the body metabolism. Thereby, a truly non-invasive infrared thermography could be used for obtaining the accurate HbA(1c) with no blood sample extraction; further, it could be used as a preferred diagnostic tool for type 2 diabetes.
    Molecular and Cellular Endocrinology 12/2012; 367(1-2). DOI:10.1016/j.mce.2012.12.017 · 4.41 Impact Factor
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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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    ABSTRACT: Histamine acts centrally to increase energy expenditure and reduce body weight by mechanisms not fully understood. It has been suggested that in the obese state hypothalamic histamine signaling is altered. Previous studies have also shown that histamine acting in the preoptic area controls thermoregulation. We aimed to study the influence of preoptic histamine on body temperature and energy homeostasis in control and obese mice. Activating histamine receptors in the preoptic area by increasing the concentration of endogenous histamine or by local injection of specific agonists induced an elevation of core body temperature and decreased respiratory exchange ratio (RER). In addition, the food intake was significantly decreased. The hyperthermic effect was associated with a rapid increase in mRNA expression of uncoupling proteins in thermogenic tissues, the most pronounced being that of uncoupling protein (UCP) 1 in brown adipose tissue and of UCP2 in white adipose tissue. In diet-induced obese mice histamine had much diminished hyperthermic effects as well as reduced effect on RER. Similarly, the ability of preoptic histamine signaling to increase the expression of uncoupling proteins was abolished. We also found that the expression of mRNA encoding the H1 receptor subtype in the preoptic area was significantly lower in obese animals. These results indicate that histamine signaling in the preoptic area modulates energy homeostasis by regulating body temperature, metabolic parameters and food intake and that the obese state is associated with a decrease in neurotransmitter's influence.
    Neuroscience 05/2012; 217:84-95. DOI:10.1016/j.neuroscience.2012.04.068 · 3.36 Impact Factor
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    • "Molecular profiling of single neurons also demonstrated that GPR83 was expressed in warm sensitive neurons (WSN) of the preoptic area of the anterior hypothalamus (POA), which are important regulators of temperature and energy homeostasis [13]. These specialized neurons participate in central thermoregulation responding to local temperature increase, pyrogens, as well as nutrient signals and can regulate the amount of energy expenditure by influencing heat dissipation [14] [15] [16] [17]. Thus, we hypothesized that GPR83 may participate in the regulation of temperature and energy homeostasis. "
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    ABSTRACT: The G protein-coupled receptor 83 (GPR83) was recently demonstrated in warm sensitive neurons (WSN) of the hypothalamic preoptic area (POA) that participate in temperature homeostasis. Thus, we investigated whether GPR83 may have a role in regulating core body temperature (CBT) by reducing its expression in the POA. Dissipation of energy in the form of heat is the primary mode of energy expenditure in mammals and can ultimately affect energy homeostasis. Thus, we also measured the level of important regulators of metabolism. Downregulation of GPR83 was obtained by lentiviral short-hairpin RNAs (shGPR83) vectors designed and selected for their ability to reduce GPR83 levels in vitro. Mice received POA injection of shGPR83 or non-silencing vectors and were monitored for CBT, motor activity, food intake body weight and circulating levels of IGF-1, insulin, leptin and adiponectin. Down-regulation of GPR83 in the POA resulted in a small (0.15°C) but significant reduction of CBT during the dark/active cycle of the day. Temperature reduction was followed by increased body weight gain independent of caloric intake. shGPR83 mice also had increased level of circulating adiponectin (31916±952pg/mL vs. 23474±1507pg/mL, P<.01) while no change was observed for insulin, IGF-1 or leptin. GPR83 may participate in central thermoregulation and the central control of circulating adiponectin. Further work is required to determine how GPR83 can affect POA WSN and what are the long term metabolic consequences of its down-regulation.
    Metabolism: clinical and experimental 05/2012; 61(10):1486-93. DOI:10.1016/j.metabol.2012.03.015 · 3.89 Impact Factor
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