1. Increased mitochondrial calcium uniporter in adipocytes underlies mitochondrial alterations associated with insulin resistance.
- Author
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Wright LE, Vecellio Reane D, Milan G, Terrin A, Di Bello G, Belligoli A, Sanna M, Foletto M, Favaretto F, Raffaello A, Mammucari C, Nitti D, Vettor R, and Rizzuto R
- Subjects
- 3T3-L1 Cells, Adult, Animals, Case-Control Studies, Diabetes Mellitus, Experimental genetics, Diabetes Mellitus, Experimental metabolism, Female, Humans, Intra-Abdominal Fat metabolism, Intra-Abdominal Fat pathology, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Mice, Transgenic, Middle Aged, Mitochondria pathology, Obesity genetics, Obesity metabolism, Obesity pathology, Prediabetic State genetics, Prediabetic State metabolism, Prediabetic State pathology, Subcutaneous Fat metabolism, Subcutaneous Fat pathology, Adipocytes metabolism, Calcium Channels genetics, Calcium Channels metabolism, Insulin Resistance physiology, Mitochondria metabolism
- Abstract
Intracellular calcium influences an array of pathways and affects cellular processes. With the rapidly progressing research investigating the molecular identity and the physiological roles of the mitochondrial calcium uniporter (MCU) complex, we now have the tools to understand the functions of mitochondrial Ca
2+ in the regulation of pathophysiological processes. Herein, we describe the role of key MCU complex components in insulin resistance in mouse and human adipose tissue. Adipose tissue gene expression was analyzed from several models of obese and diabetic rodents and in 72 patients with obesity as well as in vitro insulin-resistant adipocytes. Genetic manipulation of MCU activity in 3T3-L1 adipocytes allowed the investigation of the role of mitochondrial calcium uptake. In insulin-resistant adipocytes, mitochondrial calcium uptake increased and several MCU components were upregulated. Similar results were observed in mouse and human visceral adipose tissue (VAT) during the progression of obesity and diabetes. Intriguingly, subcutaneous adipose tissue (SAT) was spared from overt MCU fluctuations. Furthermore, MCU expression returned to physiological levels in VAT of patients after weight loss by bariatric surgery. Genetic manipulation of mitochondrial calcium uptake in 3T3-L1 adipocytes demonstrated that changes in mitochondrial calcium concentration ([Ca2+ ]mt ) can affect mitochondrial metabolism, including oxidative enzyme activity, mitochondrial respiration, membrane potential, and reactive oxygen species formation. Finally, our data suggest a strong relationship between [Ca2+ ]mt and the release of IL-6 and TNFα in adipocytes. Altered mitochondrial calcium flux in fat cells may play a role in obesity and diabetes and may be associated with the differential metabolic profiles of VAT and SAT., (Copyright © 2017 the American Physiological Society.)- Published
- 2017
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