1. Knockdown of ANT2 reduces adipocyte hypoxia and improves insulin resistance in obesity
- Author
-
Anne N. Murphy, Jin Young Huh, Pedro Cabrales, Jerrold M. Olefsky, Matthew Riopel, Gordon I. Smith, Aleksander Andreyev, Jong Bae Seo, Gautam Bandyopadhyay, Yun Sok Lee, Scott C. Beeman, Samuel Klein, and Neurosurgery
- Subjects
0301 basic medicine ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Adipose tissue ,Apoptosis ,Mitochondrion ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Adipocyte ,Adipocytes ,2.1 Biological and endogenous factors ,Aetiology ,Hypoxia ,Cancer ,ANT2 ,Chemistry ,Diabetes ,Type 2 diabetes ,Mitochondria ,Oxygen tension ,Adipose Tissue ,5.1 Pharmaceuticals ,Gene Knockdown Techniques ,Uncoupled Respiration ,Hypoxia-Inducible Factor 1 ,Development of treatments and therapeutic interventions ,medicine.symptom ,medicine.medical_specialty ,Knockout ,HIF-1α ,Inflammation ,alpha Subunit ,03 medical and health sciences ,Oxygen Consumption ,Insulin resistance ,Physiology (medical) ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Humans ,Obesity ,Metabolic and endocrine ,Insulin ,Adenine Nucleotide Translocator 2 ,Cell Biology ,Adipose Tissue Hypoxia ,Hypoxia (medical) ,medicine.disease ,Fibrosis ,Oxygen ,Glucose ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,Insulin Resistance ,030217 neurology & neurosurgery - Abstract
Decreased adipose tissue oxygen tension and increased HIF-1α expression can trigger adipose tissue inflammation and dysfunction in obesity. Our current understanding of obesity-associated decreased adipose tissue oxygen tension is mainly focused on changes in oxygen supply and angiogenesis. Here, we demonstrate that increased adipocyte O2 demand, mediated by ANT2 activity, is the dominant cause of adipocyte hypoxia. Deletion of adipocyte Ant2 improves obesity-induced intracellular adipocyte hypoxia by decreasing obesity-induced adipocyte oxygen demand, without effects on mitochondrial number or mass, or oligomycin-sensitive respiration. This led to decreased adipose tissue HIF-1α expression and inflammation with improved glucose tolerance and insulin resistance in both a preventative or therapeutic setting. Our results suggest that ANT2 may be a target for the development of insulin sensitizing drugs and that ANT2 inhibition might have clinical utility.
- Published
- 2018