Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

May 8, 2009The Journal of neuroscience : the official journal of the Society for Neuroscience

Brain GLP-1 receptor signals control body fat storage through the sympathetic nervous system, but this effect is reduced in diet-induced obesity

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Abstract

Intracerebroventricular infusion of GLP-1 in mice decreases lipid storage in white adipose tissue independent of nutrient intake.

The central GLP-1 receptor system may regulate fat storage through effects on lipid metabolism.
GLP-1 infusion was tested in both lean and diet-induced obese mice.
The sympathetic nervous system may play a role in how adipocytes respond to changes in GLP-1 levels in the brain.
In diet-induced obese mice, the modulation of adipocyte metabolism by CNS GLP-1 was reduced.
Obesity may lead to a resistance in adipocytes to the effects of CNS GLP-1 on fat metabolism.

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We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7-36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking beta-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.

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Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

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