title: Spare mitochondrial respiratory capacity permits human adipocytes to maintain ATP homeostasis under hypoglycemic conditions.
abstract: Mitochondrial dysfunction in white adipose tissue plays a key role in the pathogenesis of type 2 diabetes. Emerging evidence specifically suggests that altered oxidative phosphorylation in adipocytes may have a relevant effect on systemic glucose homeostasis, requiring understanding of adipocyte bioenergetics. We analyzed energetic flux of an intact human adipocyte cell model by plate-based respirometry and extracellular acidification. During differentiation, we discovered that glycolytic ATP production was increasingly replaced by mitochondrial oxidative metabolism (from 20 to 60%). This observation was corroborated by simultaneous up-regulation of canonical mitochondrial gene programs, such as peroxisome proliferator-activated receptor γ coactivator α (PGC1α; 150-fold) and cytochrome c-1 (CytC; 3-fold). Mimicking diabetic phenotypes by exposure to various glucose levels (0, 5, and 25 mM) resulted in immediate adjustments of glycolytic and mitochondrial activity that aimed to maintain intracellular ATP. We conclude that ATP deficits by mitochondrial failure are compensated by glycolytic ATP production, resulting in inefficient conversion of glucose to cellular ATP. Metabolic inefficiency may enhance glucose uptake, therefore improving systemic glucose homeostasis. Notably, mature adipocytes developed a high spare respiratory capacity (increased by 6-fold) permitting rapid adaptation to metabolic changes. Spare respiratory capacity may also allow additional metabolic scope for energy dissipation, potentially offering new therapeutic targets for the treatment of metabolic disease.
authors.affiliation: 2Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Institute for Diabetes and Regeneration Research, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany. michaela.keuper@helmholtz-muenchen.de.
authors.forename: Michaela
authors.initials: M
authors.lastname: Keuper
authors.forename: Martin
authors.initials: M
authors.lastname: Jastroch
authors.forename: Chun-Xia
authors.initials: CX
authors.lastname: Yi
authors.forename: Pamela
authors.initials: P
authors.lastname: Fischer-Posovszky
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Hofmann
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D003575:Cytochromes c1 / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006019:Glycolysis; D006801:Humans; D010085:Oxidative Phosphorylation; D047495:PPAR gamma / Q000378:metabolism
chemical_list: D047495:PPAR gamma; D000255:Adenosine Triphosphate; D003575:Cytochromes c1; D005947:Glucose
keywords: glycolysis; hyperglycemic; lactate secretion; oxidative phosphorylation