Mitochondrial (dys)function in adipocyte (de)differentiation and systemic metabolic alterations

Abstract

In mammals, adipose tissue, composed of BAT and WAT, collaborates in energy partitioning and performs metabolic regulatory functions. It is the most flexible tissue in the body, because it is remodeled in size and shape by modifications in adipocyte cell size and/or number, depending on developmental status and energy fluxes. Although numerous reviews have focused on the differentiation program of both brown and white adipocytes as well as on the pathophysiological role of white adipose tissues, the importance of mitochondrial activity in the differentiation or the dedifferentiation programs of adipose cells and in systemic metabolic alterations has not been extensively reviewed previously. Here, we address the crucial role of mitochondrial functions during adipogenesis and in mature adipocytes and discuss the cellular responses of white adipocytes to mitochondrial activity impairment. In addition, we discuss the increase in scientific knowledge regarding mitochondrial functions in the last 10 years and the recent suspicion of mitochondrial dysfunction in several 21st century epidemics (ie, obesity and diabetes), as well as in lipodystrophy found in HIV-treated patients, which can contribute to the development of new therapeutic strategies targeting adipocyte mitochondria.

Figure 1

Main mitochondrial functions in adipocytes. Pyruvate derived from glucose by glycolysis in the cytosol is converted, after uptake, into acetyl-CoA in the matrix. Acetyl groups pass out of the mitochondrion as citrate; in the cytosol, acetyl-CoA is released for fatty acid synthesis eventually esterified TGs. Oxaloacetate is reduced to malate, which returns to the mitochondrial matrix and is converted to oxaloacetate, a TCA cycle intermediate. Alternatively, free fatty acids are taken by the carnitine-palmitoyl-transferase-1 (CPT-1) complexes into the mitochondrial matrix and are oxidized to yield acetyl residues in the form of acetyl-CoA in a process called fatty acid β-oxidation. The acetyl groups are oxidized to CO₂ via the TCA cycle. Electrons derived from oxido-reduction reactions are finally accepted by O₂. The energy is retrieved as an electrochemical proton gradient used as the driving force for ATP synthesis. Besides, the coactivator PGC1-α contributes to both mitochondrial biogenesis in adipocytes and adipogenesis itself by activating specific transcription factors involved in the expression of nuclear genes encoding mitochondrial proteins and/or adipogenic markers. Both mitochondrial proteins and transcription factors such as mitochondrial transcription factors A and B (mtTFA and mtTFB) are imported into mitochondria by translocase outer membrane/translocase inner membrane (TOM/TIM) complexes: mtTFA and mtTFB being specifically involved in mtDNA replication. Increased mitochondrial biogenesis goes along with both an enhance ATP production and lipogenesis, whereas lipolysis is inhibited during adipocyte differentiation. OMM, outer mitochondrial membrane; IMS, intermembrane space; IMM, inner mitochondrial membrane.

Figure 2

Comparative effects of mitochondrial dysfunction in preadipocytes and in adipocytes. In preadipocytes, mitochondrial dysfunction induced by different factors such as hypoxia or mitochondrial respiration impairment (ie, using OXPHOS inhibitors) leads to impaired lipid metabolism and/or oxidation of lipids, proteins, and mtDNA, which trigger the accumulation of TGs in the cytosol of preadipocytes, a process mediated through a decrease in fatty acid β-oxidation and an increase in lipogenesis. Conversely, in adipocytes, mitochondrial dysfunction induced by factors such as HIV, HAART, aging, obesity, or T2DM leads to a decrease in ATP production, the development of insulin resistance, apoptosis, or impairment of adipogenesis. A moderate increase in cytosolic calcium concentration ([Ca²⁺]) results in the stimulation of lipogenesis and exerting an inhibitory effect on lipolysis accompanied by UCP-2 overexpression. All these effects lead to a decrease in triglyceride content mediated by a stimulation of lipolysis and a decrease in lipogenesis. POLγ, polymerase γ.