Heterotrimeric Gai2 protein function in insulin-secreting beta-cells and insulin-sensitive adipocytes

• Applicant: Professor Dr. Bernd Nürnberg
• Subject Area: Pharmacology ; Endocrinology, Diabetology, Metabolism ; Nutritional Sciences
• Term: from 2011 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 212091437

• Final Report Year: 2020

Final Report Abstract

Obesity is an increasing health problem worldwide and adipocytes are the main site of fat storage during excessive weight gain. The aim of our DFG-funded project was to provide insight into Gαi-specific functions in adipocytes and their impact in regulation of fat metabolism using genetically modified mouse models. Although several Pertussis-toxin-based studies have indicated that Gi-proteins inhibit lipolysis, the isoformspecific functions of Gαi proteins in adipocytes remained to be clarified. We employed AdipoqCreERT2 mice and generated adipocyte-specific Gnai2-deficient mice (Gnai2ako) to study Gαi2 function specifically in adipocytes. Challenging these mice with a 45% high fat diet (HFD) revealed that Gnai2ako mice gained significantly less body weight compared to littermate controls. The knockout mice showed significantly decreased fat masses, smaller adipocytes and reduced inflammation in the white adipose tissue relative to littermate controls. In addition, glucose tolerance and insulin sensitivity of HFD-fed Gnai2ako mice were improved compared to the respective controls. Absence of adipocyte Gαi2 resulted in significantly higher intracellular cAMP levels and lipolysis upon adrenergic stimulation in both, brown and white adipocytes of the mutant mice. Concomitantly, in vivo measured energy expenditure was significantly increased pointing to an isoform-specific function of Gαi2 in brown and white adipocytes. In fact, Gαi2-deficiency increased lipolytic activity of brown and white adipocytes in a cAMP-dependent manner that is likely to explain an increased energy expenditure and a significantly reduced weight gain under high caloric conditions. Importantly, none of the remaining Gαi isoforms compensated for the missing Gαi2. Preliminary studies in adipocyte-specific Gαi3-deficient mice point to an opposite effect of Gαi3 in adipocytes as compared to Gαi2. Although global deletion of Gnai3 impedes diet-induced obesity our findings suggest that adipocytes Gαi3 is not causative for the phenotype seen in the global Gnai3-deficient mice. Taken together, our studies expand knowledge of the physiological functions of the adipocyte Gαi isoforms in obesity and suggest specific inhibition of adipocyte Gαi2-dependent but not Gαi3-dependent signaling pathways to prevent excessive weight gain.

Publications

• (2015). Variation in the Phosphoinositide 3-Kinase γ Gene Affects Plasma HDL-Cholesterol without Modification of Metabolic or Inflammatory Markers. PloS one 10: e0144494
  Kächele M, Hennige AM, Machann J, Hieronimus A, Lamprinou A, Machicao F, Schick F, Fritsche A, Stefan N, Nürnberg B, Häring HU, Staiger H
  
• (2016). Obesogenic and Diabetogenic Effects of High-Calorie Nutrition Require Adipocyte BK Channels. Diabetes 65: 3621-3635
  Illison J, Tian L, McClafferty H, Werno M, Chamberlain LH, Leiss V, Sassmann A, Offermanns S, Ruth P, Shipston MJ, Lukowski R
  
• (2019). Diabetic lung disease: fact or fiction? Rev Endocr Metab Disord 20: 303-319
  Kolahian S, Leiss V, Nürnberg B
  
• (2020). Selective protection of murine cerebral Gi/o-proteins from inactivation by parenterally injected pertussis toxin. J Mol Med (Berl) 98: 97-110
  Vega SC, Leiss V, Piekorz R, Calaminus C, Pexa K, Vuozzo M, Schmid AM, Devanathan V, Kesenheimer C, Pichler BJ, Beer-Hammer S, Nürnberg B