Mice lacking PGC-1β in adipose tissues reveal a dissociation between mitochondrial dysfunction and insulin resistance

Abstract

Proper development and function of white adipose tissue (WAT), which are regulated by multiple transcription factors and coregulators, are crucial for glucose homeostasis. WAT is also the main target of thiazolidinediones, which are thought to exert their insulin-sensitizing effects by promoting mitochondrial biogenesis in adipocytes. Besides being expressed in WAT, the role of the coactivator PGC-1β in this tissue has not been addressed. To study its function in WAT, we have generated mice that lack PGC-1β in adipose tissues. Gene expression profiling analysis of WAT reveals that PGC-1β regulates mitochondrial genes involved in oxidative metabolism. Furthermore, lack of PGC-1β prevents the induction of mitochondrial genes by rosiglitazone in WAT without affecting the capacity of thiazolidinediones to enhance insulin sensitivity. Our findings indicate that PGC-1β is important for basal and rosiglitazone-induced mitochondrial function in WAT, and that induction of mitochondrial oxidative capacity is not essential for the insulin-sensitizing effects of thiazolidinediones.

GADD45γ regulates the thermogenic capacity of brown adipose tissue

“…For overexpression assays, mature adipocytes were infected on day 5 or 6 of differentiation with the indicated adenoviruses in serum-free DMEM with 2 mg/mL poly-L-lysine, at a multiplicity of infection (MOI) of 20. For the generation of Pgc-1α/Pgc-1β knockout cells, preadipocytes isolated from mice carrying floxed Ppargc1a and Ppargc1b alleles (40,41) were infected at 70% confluency with GFP (control) or CRE-expressing lentivirus, resuspended in 4 μg/mL polybrene.…”

Mitochondrial Actions for Fat Browning and Energy Expenditure in White Adipose Tissue

“…This finding is in line with a study done with PGC1β-FAT-KO mice. In this study, PGC1β deletion did not alter fat accretion or white adipocyte size, since the expression of terminal markers of adipocyte differentiation or genes encoding for proteins involved in lipid synthesis were not differentially regulated in the WAT of PGC1β-FAT-KO mice [75].…”

“…This finding is in line with a study done with PGC1β-FAT-KO mice. In this study, PGC1β deletion did not alter fat accretion or white adipocyte size, since the expression of terminal markers of adipocyte differentiation or genes encoding for proteins involved in lipid synthesis were not differentially regulated in the WAT of PGC1β-FAT-KO mice [75].It is usually considered that FFA re-esterification is the major pathway to retain FA within the adipocyte, preventing excessive release of FFA from lipolysis to circulation [76,77].Annex Publishers | www.annexpublishers.comVolume 2 | Issue 2 …”

Pharmacological induction of mitochondrial biogenesis as a therapeutic strategy for the treatment of type 2 diabetes

“…Despite the lack of PGC-1a expression in white adipocytes, rosiglitazone increases mitochondrial gene expression, mtDNA content and mitochondrial oxidative function in PGC-1a knockout mice to the same extent as in wild type animals and ameliorates glucose tolerance and insulin sensitivity [156]. In contrast, mice lacking expression of the coactivator PGC-1b in adipose tissues fail to increase mitochondrial gene expression and oxidative function in response to rosiglitazone [39]. Therefore, it appears that PGC-1b, but not PGC-1a, is the principal mediator of PPARg agonists in the regulation of mitochondrial biogenesis.…”

“…In these tissuespecific AIF knockout models, the reduction in mitochondrial function results from impaired synthesis of components of the OxPhos system, but they do not exhibit obvious alterations in mitochondrial mass or structure [38]. Finally, a new adiposespecific PGC-1b knockout mouse recently generated in our laboratory has normal glucose homeostasis despite reduced expression of mitochondrial OxPhos components in WAT and diminished mitochondrial oxidative capacity [39]. All these mouse models strongly evidence the dissociation between impaired mitochondrial biogenesis/function and the development of insulin resistance.…”