Increased mitochondrial respiration of adipocytes from metabolically unhealthy obese compared to healthy obese individuals

Anja Böhm,Hans-Ulrich Häring,Marty Zdichavsky,Tobias Meile,Andreas Fritsche,Martin Hrabě De Angelis,Michaela Keuper,Andras Franko,Harald Staiger

doi:10.1038/s41598-020-69016-9

Abstract

Among obese subjects, metabolically healthy (MHO) and unhealthy obese (MUHO) subjects exist, the latter being characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation. Insulin resistance and obesity are known to associate with alterations in mitochondrial density, morphology, and function. Therefore, we assessed mitochondrial function in human subcutaneous preadipocytes as well as in differentiated adipocytes derived from well-matched donors. Primary subcutaneous preadipocytes from 4 insulin-resistant (MUHO) versus 4 insulin-sensitive (MHO), non-diabetic, morbidly obese Caucasians (BMI > 40 kg/m2), matched for sex, age, BMI, and percentage of body fat, were differentiated in vitro to adipocytes. Real-time cellular respiration was measured using an XF24 Extracellular Flux Analyzer (Seahorse). Lipolysis was stimulated by forskolin (FSK) treatment. Mitochondrial respiration was fourfold higher in adipocytes versus preadipocytes (p = 1.6*10–9). In adipocytes, a negative correlation of mitochondrial respiration with donors’ insulin sensitivity was shown (p = 0.0008). Correspondingly, in adipocytes of MUHO subjects, an increased basal respiration (p = 0.002), higher proton leak (p = 0.04), elevated ATP production (p = 0.01), increased maximal respiration (p = 0.02), and higher spare respiratory capacity (p = 0.03) were found, compared to MHO. After stimulation with FSK, the differences in ATP production, maximal respiration and spare respiratory capacity were blunted. The differences in mitochondrial respiration between MUHO/MHO were not due to altered mitochondrial content, fuel switch, or lipid metabolism. Thus, despite the insulin resistance of MUHO, we could clearly show an elevated mitochondrial respiration of MUHO adipocytes. We suggest that the higher mitochondrial respiration reflects a compensatory mechanism to cope with insulin resistance and its consequences. Preserving this state of compensation might be an attractive goal for preventing or delaying the transition from insulin resistance to overt diabetes.

Highlights

Among obese subjects, metabolically healthy (MHO) and unhealthy obese (MUHO) subjects exist, the latter being characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation
Irisin was demonstrated to inhibit adipogenesis and simulated the browning of white adipocytes, which is associated with increased mitochondrial b iogenesis[50]. These results suggest that the observed difference in mitochondrial performance between MHO and metabolically unhealthy obesity (MUHO) adipocytes could be partly regulated by adipo- and myokines, which were beyond the scope of our study
Strategies to provide higher oxidative capacity by remodeling white adipocytes into energy-dissipating brownlike adipocytes, or by recruitment of brown adipose tissue in human adults, are currently intensively investigated. This is the first study to investigate mitochondrial respiration in MHO versus MUHO adipocytes from otherwise healthy individuals, dissecting insulin resistance from obesity

Summary

Introduction

Metabolically healthy (MHO) and unhealthy obese (MUHO) subjects exist, the latter being characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation. Primary subcutaneous preadipocytes from 4 insulin-resistant (MUHO) versus 4 insulin-sensitive (MHO), non-diabetic, morbidly obese Caucasians (BMI > 40 kg/m2), matched for sex, age, BMI, and percentage of body fat, were differentiated in vitro to adipocytes. We suggest that the higher mitochondrial respiration reflects a compensatory mechanism to cope with insulin resistance and its consequences. Independent of obesity, electron transport chain genes were reduced in visceral adipose tissue from women with type 2 diabetes compared to healthy c ontrols[10]. Metabolically healthy (MHO) and metabolically unhealthy obesity (MUHO) are k nown[13]; the latter, affecting ~ 70% of obese subjects, is characterized by whole-body insulin resistance, ectopic lipid deposition, and subclinical inflammation[14,15]

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Conclusion