GLP-1 Agonism Stimulates Brown Adipose Tissue Thermogenesis and Browning Through Hypothalamic AMPK

Jun 12, 2014Diabetes

GLP-1 activation increases heat production and fat burning by affecting energy control in the brain

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Abstract

Central injection of liraglutide significantly stimulates brown adipose tissue thermogenesis in mice.

Liraglutide, a GLP-1 receptor agonist, activates brown adipose tissue thermogenesis and adipocyte browning without the need for food intake.
The hypothalamic ventromedial nucleus (VMH) is identified as a critical area for these actions.
Activation of AMPK in the VMH can inhibit the thermogenic and browning effects induced by liraglutide.
In a longitudinal study of obese type 2 diabetic patients, GLP-1 receptor agonists increased energy expenditure over one year.
Body weight reduction from liraglutide injections in other hypothalamic regions is primarily linked to decreased food intake.
While the results focus on hypothalamic mechanisms, potential influences from other brain areas are not ruled out.

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GLP-1 receptor (GLP-1R) is widely located throughout the brain, but the precise molecular mechanisms mediating the actions of GLP-1 and its long-acting analogs on adipose tissue as well as the brain areas responsible for these interactions remain largely unknown. We found that central injection of a clinically used GLP-1R agonist, liraglutide, in mice stimulates brown adipose tissue (BAT) thermogenesis and adipocyte browning independent of nutrient intake. The mechanism controlling these actions is located in the hypothalamic ventromedial nucleus (VMH), and the activation of AMPK in this area is sufficient to blunt both central liraglutide-induced thermogenesis and adipocyte browning. The decreased body weight caused by the central injection of liraglutide in other hypothalamic sites was sufficiently explained by the suppression of food intake. In a longitudinal study involving obese type 2 diabetic patients treated for 1 year with GLP-1R agonists, both exenatide and liraglutide increased energy expenditure. Although the results do not exclude the possibility that extrahypothalamic areas are also modulating the effects of GLP-1R agonists, the data indicate that long-acting GLP-1R agonists influence body weight by regulating either food intake or energy expenditure through various hypothalamic sites and that these mechanisms might be clinically relevant.

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GLP-1 Agonism Stimulates Brown Adipose Tissue Thermogenesis and Browning Through Hypothalamic AMPK

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