Adipose Mitochondrial Biogenesis Is Suppressed in db/db and High-Fat Diet–Fed Mice and Improved by Rosiglitazone

Abstract

The objective of this study was to further establish and confirm the relationship of adipose mitochondrial biogenesis in diabetes/obesity and the effects of rosiglitazone (RSG), a peroxisome proliferator-activated receptor (PPAR) ␥ agonist, by systematically analyzing mitochondrial gene expression and function in two mouse models of obesity and type 2 diabetes. Using microarray technology, adipose mitochondrial gene transcription was studied in db/db, high-fat diet-fed C57BL/6 (HFD) and respective control mice with or without RSG treatment. The findings were extended using mitochondrial staining, DNA quantification, and measurements of citrate synthase activity. In db/db and HFD mice, gene transcripts associated with mitochondrial ATP production, energy uncoupling, mitochondrial ribosomal proteins, outer and inner membrane translocases, and mitochondrial heat-shock proteins were decreased in abundance, compared with db/؉ and standardfat diet-fed control mice, respectively. RSG dose-dependently increased these transcripts in both db/db and HFD mice and induced transcription of mitochondrial structural proteins and cellular antioxidant enzymes responsible for removal of reactive oxygen species generated by increased mitochondrial activity. Transcription factors, including PPAR coactivator (PGC)-1␤, PGC-1␣, estrogen-related receptor ␣, and PPAR␣, were suppressed in both models and induced by RSG. The effects of RSG on adipose mitochondrial genes were confirmed by quantitative RT-PCR and further supported by mitochondrial staining, mitochondrial DNA quantification, and citrate synthase activity. Adipose mitochondrial biogenesis was overwhelmingly suppressed in both mouse models of diabetes/obesity and globally induced by RSG. These findings suggest an important role of adipose mitochondria in diabetes/obesity and the potential for new treatment approaches targeting adipose mitochondria. Diabetes 56:1751-1760, 2007 P eroxisome proliferator-activated receptor (PPAR) ␥ agonists, including rosiglitazone (RSG), are effective drugs for the treatment of type 2 diabetes. It is well established that RSG induces adipogenesis and causes body-wide lipid repartitioning by increasing adipose triglyceride content, thereby lowering free fatty acids, glycerol, triglycerides, and glucose in the circulation, which is associated with increased insulin sensitivity of the liver, muscle, and other organs. Critical to this process, adipose tissue, which highly expresses PPAR␥, serves not only as a lipid storage depot but also as an endocrine organ producing adipokines that regulate the activity of other tissues (rev. in 1,2).There has been growing interest in exploring the involvement of adipose mitochondria in the regulation of whole-body energy homeostasis (3-9). Recent studies suggest that diabetes/obesity is accompanied by a decrease in the expression of adipose mitochondrial genes in ob/ob mice (8) and impaired adipose mitochondria in db/db mice (9) and that the compromised mitochondrial conditions in ob/ob and db/db mice were reversi...

BNIP3 is essential for mitochondrial bioenergetics during adipocyte remodelling in mice

“…Regulation of BNIP3 during adipocyte remodelling, especially in obesity or PPARγ-related conditions The role of BNIP3 has been mostly investigated in myocytes in relation to hypoxia-induced apoptotic cell death and autophagic cell survival [14]. Here, we revealed that a considerable amount of BNIP3 expression is regulated in adipocytes under conditions in which higher mitochondrial content is required, including adipocyte differentiation [10], starvation [25] and in BAT [26], and also by rosiglitazone treatment [2,7,10]. We also found that BNIP3 was downregulated in adipose tissue under obese diabetic conditions.…”

“…Within adipocytes, mitochondria show robust changes in density and morphology under pathophysiological conditions [2,3]. Excess mitochondria occur with myopathy or cancer [4] and reduced mitochondria number and/or function is associated with obesity [5][6][7]. This suggests that tight quality control of the mitochondria may be critical for maintaining adipocyte function during adipocyte remodelling.…”

“…Agonists of PPARγ improve insulin resistance, probably by stimulating the storage of excess energy as fat, thus improving blood glucose [9]. Many studies have also reported that PPARγ agonists induce mitochondrial biogenesis [2,7,10,11]. Based on the critical role of mitochondria in energy generation, mitochondrial biogenesis may contribute to PPARγ-agonist-induced improvement in insulin resistance [12].…”

Fine-tuned iron availability is essential to achieve optimal adipocyte differentiation and mitochondrial biogenesis

“…Reduced mitochondrial mass and function has been found in adipose tissue of ob/ob and db/db mice and in adipose tissue from obese individuals with type 2 diabetes in association with increased activity of several inflammatory pathways [18][19][20][21][22][23][24]. Given previous findings in whole adipose tissue, we hypothesised that iron might have an important role in adipogenesis, and we decided to explore in greater depth which cells are responsible for the altered expression of genes involved in iron metabolism and to investigate the precise role of iron in adipocyte differentiation.…”

Age-dependent obesity and mitochondrial dysfunction

“…These findings seem to contrast with the general mitochondrial dysfunction described previously in the WAT of HFD-fed mice, or in mice with altered leptin signaling, such as ob/ob and db/db obese mice. [16][17][18] However, it could be considered that a global decline in mitochondrial content would require not only WAT expansion, but also the development of an obesity-driven inflammatory milieu provoked by HFD/ nutrient overload. Indeed, inflammatory mediators are associated with a decline in mitochondrial content 17,[19][20][21] and presumably this inflammatory process does not occur-or occurs to a lesser extent-in aging WAT.…”