Short Term Voluntary Overfeeding Disrupts Brain Insulin Control of Adipose Tissue Lipolysis

Thomas Scherer,Claudia Lindtner,Elizabeth Zielinski,James O'Hare,Nika Filatova,Christoph Buettner

doi:10.1074/jbc.m111.307348

Thomas Scherer, Claudia Lindtner + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m111.307348

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Abstract

Insulin controls fatty acid (FA) release from white adipose tissue (WAT) through direct effects on adipocytes and indirectly through hypothalamic signaling by reducing sympathetic nervous system outflow to WAT. Uncontrolled FA release from WAT promotes lipotoxicity, which is characterized by inflammation and insulin resistance that leads to and worsens type 2 diabetes. Here we tested whether early diet-induced insulin resistance impairs the ability of hypothalamic insulin to regulate WAT lipolysis and thus contributes to adipose tissue dysfunction. To this end we fed male Sprague-Dawley rats a 10% lard diet (high fat diet (HFD)) for 3 consecutive days, which is known to induce systemic insulin resistance. Rats were studied by euglycemic pancreatic clamps and concomitant infusion of either insulin or vehicle into the mediobasal hypothalamus. Short term HFD feeding led to a 37% increase in caloric intake and elevated base-line free FAs and insulin levels compared with rats fed regular chow. Overfeeding did not impair insulin signaling in WAT, but it abolished the ability of mediobasal hypothalamus insulin to suppress WAT lipolysis and hepatic glucose production as assessed by glycerol and glucose flux. HFD feeding also increased hypothalamic levels of the endocannabinoid 2-arachidonoylglycerol after only 3 days. In summary, overfeeding impairs hypothalamic insulin action, which may contribute to unrestrained lipolysis seen in human obesity and type 2 diabetes.

Highlights

Insulin suppresses lipolysis through direct effects on adipocytes and indirectly through its neuronal receptors by reducing sympathetic outflow to adipose tissue
Overfeeding did not impair insulin signaling in white adipose tissue (WAT), but it abolished the ability of mediobasal hypothalamus insulin to suppress WAT lipolysis and hepatic glucose production as assessed by glycerol and glucose flux
We show that only 3 days of overfeeding in SD rats is sufficient to severely impair the ability of hypothalamic insulin to suppress WAT lipolysis

Summary

Background

Insulin suppresses lipolysis through direct effects on adipocytes and indirectly through its neuronal receptors by reducing sympathetic outflow to adipose tissue. We tested whether early diet-induced insulin resistance impairs the ability of hypothalamic insulin to regulate WAT lipolysis and contributes to adipose tissue dysfunction To this end we fed male Sprague-Dawley rats a 10% lard diet (high fat diet (HFD)) for 3 consecutive days, which is known to induce systemic insulin resistance. Overfeeding did not impair insulin signaling in WAT, but it abolished the ability of mediobasal hypothalamus insulin to suppress WAT lipolysis and hepatic glucose production as assessed by glycerol and glucose flux. Because impaired hypothalamic insulin action can unrestrain WAT lipolysis [13], the increased FA flux could in turn contribute to a failure of insulin to suppress hepatic GP. Overfeeding Impairs Brain Insulin Action term overfeeding alters WAT and hepatic insulin action and whether this is associated with impaired hypothalamic insulin action

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION