3-Hydroxyisobutyrate, A Strong Marker of Insulin Resistance in Type 2 Diabetes and Obesity That Modulates White and Brown Adipocyte Metabolism
Open Access
- 25 June 2020
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 69 (9), 1903-1916
- https://doi.org/10.2337/db19-1174
Abstract
Circulating branched-chain amino acids (BCAAs) associate with insulin resistance and type 2 diabetes. 3-Hydroxyisobutyrate (3-HIB) is a catabolic intermediate of the BCAA valine. In this study, we show that in a cohort of 4,942 men and women, circulating 3-HIB is elevated according to levels of hyperglycemia and established type 2 diabetes. In complementary cohorts with measures of insulin resistance, we found positive correlates for circulating 3-HIB concentrations with HOMA2 of insulin resistance, as well as a transient increase in 3-HIB followed by a marked decrease after bariatric surgery and weight loss. During differentiation, both white and brown adipocytes upregulate BCAA utilization and release increasing amounts of 3-HIB. Knockdown of the 3-HIB–forming enzyme 3-hydroxyisobutyryl-CoA hydrolase decreases release of 3-HIB and lipid accumulation in both cell types. Conversely, addition of 3-HIB to white and brown adipocyte cultures increases fatty acid uptake and modulated insulin-stimulated glucose uptake in a time-dependent manner. Finally, 3-HIB treatment decreases mitochondrial oxygen consumption and generation of reactive oxygen species in white adipocytes, while increasing these measures in brown adipocytes. Our data establish 3-HIB as a novel adipocyte-derived regulator of adipocyte subtype-specific functions strongly linked to obesity, insulin resistance, and type 2 diabetes.Keywords
Funding Information
- Norges Forskningsråd (263124/F20)
- Diabetesforbundet
This publication has 47 references indexed in Scilit:
- Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fatNature Medicine, 2013
- The nuclear receptors NUR77, NURR1 and NOR1 in obesity and during fat lossInternational Journal of Obesity, 2011
- Respiration in Adipocytes is Inhibited by Reactive Oxygen SpeciesObesity, 2010
- Adipose Tissue Branched Chain Amino Acid (BCAA) Metabolism Modulates Circulating BCAA Levels*Online Journal of Public Health Informatics, 2010
- A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin ResistanceCell Metabolism, 2009
- Reassessing triglyceride synthesis in adipose tissueTrends in Endocrinology & Metabolism, 2008
- Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolismAmerican Journal of Physiology-Endocrinology and Metabolism, 2007
- Is There a Simple Way to Identify Insulin-Resistant Individuals at Increased Risk of Cardiovascular Disease?The American Journal of Cardiology, 2005
- Coordinated Expression of Valine Catabolic Enzymes During Adipogenesis: Analysis of Activity, mRNA, Protein Levels, and Metabolic ConsequencesArchives of Biochemistry and Biophysics, 1994
- Ethanol and oleate inhibition of α-ketoisovalerate and 3-hydroxyisobutyrate metabolism by isolated hepatocytesArchives of Biochemistry and Biophysics, 1992