Lack of Adipocyte AMPK Exacerbates Insulin Resistance and Hepatic Steatosis through Brown and Beige Adipose Tissue Function

Emilio P Mottillo; Eric M Desjardins; Justin D Crane; Brennan K Smith; Alex E Green; Serge Ducommun; Tora I Henriksen; Irena A Rebalka; Aida Razi; Kei Sakamoto; Camilla Scheele; Bruce E Kemp; Thomas J Hawke; Joaquin Ortega; James G Granneman; Gregory R Steinberg

doi:10.1016/j.cmet.2016.06.006

Lack of Adipocyte AMPK Exacerbates Insulin Resistance and Hepatic Steatosis through Brown and Beige Adipose Tissue Function

Cell Metab. 2016 Jul 12;24(1):118-29. doi: 10.1016/j.cmet.2016.06.006.

Authors

Emilio P Mottillo¹, Eric M Desjardins¹, Justin D Crane¹, Brennan K Smith¹, Alex E Green¹, Serge Ducommun², Tora I Henriksen³, Irena A Rebalka⁴, Aida Razi⁵, Kei Sakamoto², Camilla Scheele⁶, Bruce E Kemp⁷, Thomas J Hawke⁴, Joaquin Ortega⁵, James G Granneman⁸, Gregory R Steinberg⁹

Affiliations

¹ Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
² Nestlé Institute of Health Sciences SA, EPFL Innovation Park, Lausanne, Switzerland.
³ The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
⁴ Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
⁵ Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
⁶ The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen N, Denmark.
⁷ St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Victoria 3065, Australia; Mary MacKillop Institute for Health Research Australian Catholic University, Victoria Parade, Fitzroy, Victoria 3065, Australia.
⁸ Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit 48201, MI, USA.
⁹ Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada. Electronic address: gsteinberg@mcmaster.ca.

Abstract

Brown (BAT) and white (WAT) adipose tissues play distinct roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. The AMP-activated protein kinase (AMPK) is a cellular energy sensor, but its role in regulating BAT and WAT metabolism is unclear. We generated an inducible model for deletion of the two AMPK β subunits in adipocytes (iβ1β2AKO) and found that iβ1β2AKO mice were cold intolerant and resistant to β-adrenergic activation of BAT and beiging of WAT. BAT from iβ1β2AKO mice had impairments in mitochondrial structure, function, and markers of mitophagy. In response to a high-fat diet, iβ1β2AKO mice more rapidly developed liver steatosis as well as glucose and insulin intolerance. Thus, AMPK in adipocytes is vital for maintaining mitochondrial integrity, responding to pharmacological agents and thermal stress, and protecting against nutrient-overload-induced NAFLD and insulin resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism*
Adipocytes / drug effects
Adipocytes / enzymology*
Adipose Tissue, Beige / drug effects
Adipose Tissue, Beige / enzymology*
Adipose Tissue, Brown / drug effects
Adipose Tissue, Brown / enzymology*
Adipose Tissue, White / drug effects
Adipose Tissue, White / metabolism
Animals
Diet, High-Fat
Enzyme Activation / drug effects
Fatty Liver / enzymology*
Fatty Liver / pathology
Gene Deletion
Homeostasis / drug effects
Insulin Resistance*
Lipolysis / drug effects
Liver / drug effects
Liver / metabolism
Mice, Inbred C57BL
Mitochondria / drug effects
Mitochondria / metabolism
Mitochondria / ultrastructure
Norepinephrine / pharmacology
Thermogenesis / drug effects

Substances

AMP-Activated Protein Kinases
Norepinephrine

Abstract

Publication types

MeSH terms

Substances

Grants and funding