HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue

Abstract

Objective Insulin regulates mitochondrial function, thereby propagating an efficient metabolism. Conversely, diabetes and insulin resistance are linked to mitochondrial dysfunction with a decreased expression of the mitochondrial chaperone HSP60. The aim of this investigation was to determine the effect of a reduced HSP60 expression on the development of obesity and insulin resistance. Methods Control and heterozygous whole-body HSP60 knockout (Hsp60 +/− ) mice were fed a high-fat diet (HFD, 60% calories from fat) for 16 weeks and subjected to extensive metabolic phenotyping. To understand the effect of HSP60 on white adipose tissue, microarray analysis of gonadal WAT was performed, ex vivo experiments were performed, and a lentiviral knockdown of HSP60 in 3T3-L1 cells was conducted to gain detailed insights into the effect of reduced HSP60 levels on adipocyte homeostasis. Results Male Hsp60 +/− mice exhibited lower body weight with lower fat mass. These mice exhibited improved insulin sensitivity compared to control, as assessed by Matsuda Index and HOMA-IR. Accordingly, insulin levels were significantly reduced in Hsp60 +/− mice in a glucose tolerance test. However, Hsp60 +/− mice exhibited an altered adipose tissue metabolism with elevated insulin-independent glucose uptake, adipocyte hyperplasia in the presence of mitochondrial dysfunction, altered autophagy, and local insulin resistance. Conclusions We discovered that the reduction of HSP60 in mice predominantly affects adipose tissue homeostasis, leading to beneficial alterations in body weight, body composition, and adipocyte morphology, albeit exhibiting local insulin resistance.

The Roles of Heat Shock Protein-60 and 70 and Inflammation in Obesity-Related Kidney Disease

“…Hauffe et al demonstrated that decreased HSP-60 levels in mice result in beneficial changes in adipose tissue morphology, body weight, and insulin resistance [26]. We came to a similar conclusion in this study because of the elevated HSP-60 levels in the patient group and the relationship between this elevation and proteinuria and inflammatory markers.…”

Chaperonin counteracts diet-induced non-alcoholic fatty liver disease by aiding sirtuin 3 in the control of fatty acid oxidation

“…Eight-week-old Hsp60-Tg FVB mice fed with an HFD for 6 months had lower levels of indicators of metabolic disorders (which include overweight status, glucose intolerance, insulin resistance, hypertriglyceridaemia, increased adiposity and hepatic steatosis). Previous studies have shown that 4-week-old C57BL/6N mice deficient in ubiquitous HSP60 had less obesity and fat mass than control mice upon HFD feeding for 16 weeks [35], whereas mice with hypothalamus-specific HSP60 knockout were insulin resistant [8]. We, thus, speculated that the role of HSP60 in metabolic disease development may be tissue context-dependent, and that mice with different genetic backgrounds or ages may have differing energy demands or fat metabolism capacities.…”

Exploring the role of epicardial adipose-tissue-derived extracellular vesicles in cardiovascular diseases

“…HSP60 is a mitochondrial chaperone protein with anti-inflammatory effects, whose loss determines mitochondrial functionality impairment, a known abnormality at the basis of cardiac insulin resistance and diabetic cardiomyopathy. 113 …”