Adipocyte pseudohypoxia suppresses lipolysis and facilitates benign adipose tissue expansion.
Prolyl hydroxylase enzymes (PHDs) sense cellular oxygen upstream of hypoxia-inducible factor (HIF) signaling, leading to HIF degradation in normoxic conditions. In this study, we demonstrate that adipose PHD2 inhibition plays a key role in the suppression of adipocyte lipolysis. Adipose Phd2 gene ablation in mice enhanced adiposity, with a parallel increase in adipose vascularization associated with reduced circulating nonesterified fatty acid levels and normal glucose homeostasis. Phd2 gene-depleted adipocytes exhibited lower basal lipolysis in normoxia and reduced β-adrenergic-stimulated lipolysis in both normoxia and hypoxia. A selective PHD inhibitor suppressed lipolysis in murine and human adipocytes in vitro and in vivo in mice. PHD2 genetic ablation and pharmacological inhibition attenuated protein levels of the key lipolytic effectors hormone-sensitive lipase and adipose triglyceride lipase (ATGL), suggesting a link between adipocyte oxygen sensing and fatty acid release. PHD2 mRNA levels correlated positively with mRNA levels of AB-hydrolase domain containing-5, an activator of ATGL, and negatively with mRNA levels of lipid droplet proteins, perilipin, and TIP47 in human subcutaneous adipose tissue. Therapeutic pseudohypoxia caused by PHD2 inhibition in adipocytes blunts lipolysis and promotes benign adipose tissue expansion and may have therapeutic applications in obesity or lipodystrophy.
Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, U.K. University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, U.K. v1zmicha@staffmail.ed.ac.uk.
Zoi
Z
Michailidou
University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, U.K.
Nicholas M
NM
Morton
CIBERobn "Pathophysiology of Obesity and Nutrition," Biomedical Research Institute of Girona (IDIBGI), Girona, Spain.
José Maria
JM
Moreno Navarrete
University of Edinburgh/MRC Centre for Regenerative Medicine, Edinburgh, U.K.
Christopher C
CC
West
The Department of Plastic, Reconstructive and Burns Surgery, St. Johns Hospital, Livingston, U.K.
Kenneth J
KJ
Stewart
CIBERobn "Pathophysiology of Obesity and Nutrition," Biomedical Research Institute of Girona (IDIBGI), Girona, Spain.
José Manuel
JM
Fernández-Real
Chemistry Research Laboratory, Oxford University, Oxford, U.K.
Christopher J
CJ
Schofield
University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, U.K.
Jonathan R
JR
Seckl
Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, U.K.
Peter J
PJ
Ratcliffe
D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000166:cytology* / Q000378:metabolism; D000328:Adult; D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D008049:Lipase / Q000378:metabolism; D008066:Lipolysis / Q000502:physiology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D000217:Acyltransferases
D005230:Fatty Acids, Nonesterified; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008049:Lipase; C490189:Egln1 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases