The Central Insulin System and Energy Balance

Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, OH 45237, USA.
Handbook of experimental pharmacology 01/2012; 209(209):111-29. DOI: 10.1007/978-3-642-24716-3_5
Source: PubMed


Insulin acts throughout the body to reduce circulating energy and to increase energy storage. Within the brain, insulin produces a net catabolic effect by reducing food intake and increasing energy expenditure; this is evidenced by the hypophagia and increased brown adipose tissue sympathetic nerve activity induced by central insulin infusion. Reducing the activity of the brain insulin system via administration of insulin antibodies, receptor antisense treatment, or receptor knockdown results in hyperphagia and increased adiposity. However, despite decades of research into the role of central insulin in food intake, many questions remain to be answered, including the underlying mechanism of action.

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    • "These effects depend, at least in part, on the ability of insulin to act within the central 52 nervous system to inhibit food intake (Begg and Woods 2012; Obici et al. 2002), alter 53 hepatic glucose production (Kalsbeek et al. 2010), elevate sympathetic nerve activity 54 (SNA) (Anderson et al. 1991; Luckett et al. 2013; Morgan et al. 1993; Muntzel et al. 55 1994a; Ward et al. 2011), and alter baroreflex function (Pricher et al. 2008; Young et al. 56 2010). Accumulating evidence indicates that insulin activates the PI3K-Akt signaling 57 pathway within neurons of the hypothalamic arcuate nucleus (ARC) to modulate the 58 activity of several hypothalamic pathways. "
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    ABSTRACT: Insulin acts within the central nervous system to regulate food intake and sympathetic nerve activity (SNA). Strong evidence indicates that glucocorticoids impair insulin-mediated glucose uptake and food intake. However, few data are available regarding whether glucocorticoids also modulate the sympathoexcitatory response to insulin. Therefore, the present study first confirmed that chronic administration of glucocorticoids attenuated insulin-induced increases in SNA and then investigated whether these effects were attributed to deficits in central insulin-mediated responses. Male Sprague-Dawley rats were given access to water or a drinking solution of the glucocorticoid agonist dexamethasone (0.3 μg/mL) for 7 days. A hyperinsulinemic-euglycemic clamp significantly increased lumbar SNA in control rats. This response was significantly attenuated in rats given access to dexamethasone for 7, but not 1, days. Similarly, injection of insulin into the lateral ventricle or locally within the ARC significantly increased lumbar SNA in control rats but this response was absent in rats given access to dexamethasone. The lack of a sympathetic response to insulin cannot be attributed to a generalized depression of sympathetic function or inactivation of ARC neurons as electrical activation of sciatic afferents or ARC injection of gabazine, respectively, produced similar increases in SNA between control and dexamethasone-treated rats. Western blot analysis indicates insulin produced similar activation of Akt Ser(473) and rpS6(S240/244) in the ventromedial hypothalamus of control and dexamethasone-treated rats. Collectively, these findings suggest that dexamethasone attenuates the sympathoexcitatory actions of insulin through a disruption of ARC neuronal function downstream of Akt or mTOR signaling.
    Journal of Neurophysiology 09/2014; 112(10). DOI:10.1152/jn.00514.2014 · 2.89 Impact Factor
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    • "Thus, it seems plausible that insulin may promote adipose tissue accrual via these processes. In addition, insulin may affect hunger/satiety and thereby food intake via central or peripheral actions [9,10]. However, the effect of insulin on voluntary food intake in humans is complex, and neither its actions nor their mechanisms have been entirely elucidated [11]. "
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    ABSTRACT: Background Risk for obesity differs with ethnicity/race and is associated with insulin sensitivity (SI), insulin responsiveness, and dietary glycemic load (GL). The objective of this study was to test the hypotheses that, 1) obesity-prone, normal weight, African-American (AA) women would be more insulin sensitive than BMI-matched, never overweight AA women; 2) increased adiposity over time would be associated with greater baseline SI and higher dietary GL in AA but not European-American (EA) women; and 3) increased adiposity over time would be predicted by SI in women with high but not low acute insulin response to glucose (AIRg). Methods Two controlled weight loss interventions were conducted involving overweight (BMI 25.0-29.9 kg/m2) premenopausal AA and EA women. The first included matching with normal-weight (BMI <25.0 kg/m2) controls following weight loss, and then comparing SI. The second included a 1-year follow-up of weight-reduced participants to identify predictors of change in %body fat. Main outcome measure in the first study was insulin sensitivity (SI) as assessed with intravenous glucose tolerance test (IVGTT), and in the second study was change in %fat, as assessed with DXA, over one year. AIRg was assessed during IVGTT, and free-living diet was determined by food record. Results In the first study, formerly overweight AA women were 43% more insulin sensitive than BMI-matched never overweight AA (P < 0.05). In the second study, SI was positively associated with change in %fat over 1 year only in AA women (P < 0.05) and women with high AIRg (P < 0.05). In addition, AA who were insulin sensitive and who consumed a higher GL diet tended to gain greater %fat (P = 0.086 for diet x SI interaction). In both studies, AA women had higher AIRg (P < 0.001) than EA women. Conclusions Formerly overweight (obesity-prone) AA women were more insulin sensitive than never overweight AA women, a quality that may predispose to adiposity, particularly when combined with a high GL diet. This ethnicity/race-specific effect may be due to high insulin responsiveness among AA.
    Nutrition & Metabolism 01/2013; 10(1):3. DOI:10.1186/1743-7075-10-3 · 3.26 Impact Factor
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    • "One of the mechanisms mediating apoE's anorectic action in the hypothalamus is increased PI3K/Akt signaling, which is the same signaling pathway activated by insulin (Niswender et al., 2003). Insulin plays an important role in the control of energy and glucose homeostasis (Begg and Woods, 2012; Ryan et al., 2012), and determining whether insulin's catabolic actions in the brain are related to the increased brain apoE, how apoE is up-regulated by systemic insulin, and from which brain tissue the increased apoE is secreted or produced are interesting studies for the future. "
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    ABSTRACT: Cerebrospinal fluid (CSF) provides an invaluable analytical window to the central nervous system (CNS) because it reflects the dynamically changing complement of CNS constituents. We describe an improved method for sampling CSF in rats that is easy to perform. It has a 96% success rate of CSF collection and consistently yields large volumes (150-200 μl) of CSF. The blood contamination rate is also low (6%) as determined by both visual inspection and the lack of molecular detection of apolipoprotein B, a plasma-derived protein, which is absent in the CNS. This improved method of CSF sampling can have broad applicability in physiological and pharmacological evaluation for diverse CNS targets. We used this technique to provide proof of principle by examining the effect of intraperitoneal insulin on the level of apolipoprotein E (apoE) in the CSF. Insulin (0.5 and 1 U/kg) led to a significant increase of insulin in both plasma and CSF at 2 h after intraperitoneal administration and decreased blood glucose for at least 2h. ApoE concentrations in CSF, but not in plasma, were also significantly increased, and its time-course was inversely correlated with the alterations in blood glucose over 2 h. These results provide a pharmacological validation of the novel CSF sampling and validation procedure for sampling rat CSF.
    Journal of Neuroscience Methods 06/2012; 209(1):106-12. DOI:10.1016/j.jneumeth.2012.05.034 · 2.05 Impact Factor
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