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

  1. Ruben Nogueiras1,2
  1. 1Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
  2. 2CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
  3. 3Department of Morphological Sciences, School of Medicine, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
  4. 4Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain
  5. 5Department of Biochemistry and Molecular Biology and Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain
  6. 6Department of Clinical Science, K.G. Jebsen Center for Diabetes Research, University of Bergen, Bergen, Norway
  7. 7Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
  1. Corresponding author: Ruben Nogueiras, ruben.nogueiras{at}usc.es.

Abstract

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.

  • Received February 21, 2014.
  • Accepted April 30, 2014.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.