Upregulation of peroxisome proliferator-activated receptor gamma coactivator gene (PGC1A) during weight loss is related to insulin sensitivity but not to energy expenditure

Abstract

Aims/hypothesis We investigated whether skeletal muscle peroxisome proliferator-activated receptor gamma coactivator-1 (PGC1A; also known as PPARGC1A) and its target mitofusin-2 (MFN2), as well as carnitine palmitoyltransferase-1 (CPT1; also known as carnitine palmitoyltransferase 1A [liver] [CPT1A]) and uncoupling protein (UCP)3, are involved in the improvement of insulin resistance and/or in the modification of energy expenditure during surgically induced massive weight loss. Materials and methods Seventeen morbidly obese women (mean BMI: 45.9±4 kg/m 2 ) were investigated before, and 3 and 12 months after, Roux-en-Y gastric bypass (RYGB). We evaluated insulin sensitivity by the euglycaemic-hyperinsulinaemic clamp, energy expenditure and substrate oxidation by indirect calorimetry, and muscle mRNA expression by PCR.Results Post-operatively, PGC1A was enhanced at 3 ( p= 0.02) and 12 months ( p=0.03) as was MFN2 ( p=0.008 and p=0.03 at 3 and 12 months respectively), whereas UCP3 was reduced ( p=0.03) at 12 months. CPT1 did not change. The expression of PGC1A and MFN2 were strongly ( p< 0.0001) related. Insulin sensitivity, which increased after surgery ( p=0.002 at 3, p=0.003 at 12 months), was significantly related to PGC1A and MFN2, but only MFN2 showed an independent influence in a multiple regression analysis. Energy expenditure was reduced at 3 months postoperatively ( p=0.001 vs before RYGB), remaining unchanged thereafter until 12 months. CPT1 and UCP3 were not significantly related to the modifications of energy expenditure or of lipid oxidation rate. Conclusions/interpretation Weight loss upregulates PGC1A, which in turn stimulates MFN2 expression. MFN2 expression significantly and independently contributes to the improvement of insulin sensitivity. UCP3 and CPT1 do not seem to influence energy expenditure after RYGB.

Genes involved in mitochondrial biogenesis/function are induced in response to bilio-pancreatic diversion in morbidly obese individuals with normal glucose tolerance but not in type 2 diabetic patients

“…In this study we have demonstrated that MFN2 is upregulated in skeletal muscle from morbidly obese NGT patients in response to BPD, which correlates positively with glucose oxidation. This is in keeping with previous findings observed in women subjected to BPD [18] or in patients in whom weight loss was induced by Roux-en-Y gastric bypass [32]. Our data additionally indicate that MFN2 expression is a good predictor of fasting glucose oxidation in NGT patients, much better than the expression of genes encoding for regulators of mitochondrial biogenesis such as PGC-1α or PGC-1β, and also better than the expression of genes encoding for constitutive proteins such as porin or citrate synthase (and therefore markers of mitochondrial mass).…”

“…Increased PGC-1α expression has also been reported in muscle from obese patients after weight loss induced by Roux-en-Y gastric bypass [32]. In contrast, PGC-1α, PGC-1β, PPAR-δ and SIRT1 were not induced in morbidly obese type 2 diabetic patients in response to BPD, which explains the lack of stimulation of genes encoding for mitochondrial proteins (citrate synthase, porin or MFN2) and the blunted changes of glucose and lipid oxidation particularly under fasting conditions.…”

Enhanced insulin signaling in human skeletal muscle and adipose tissue following gastric bypass surgery

“…Insulin resistance is a phenotype of obesity and type 2 diabetes, and we (5) and others (7,10,11,20) have previously reported improved peripheral glucose disposal rates following RYGB, in both subjects with normal glucose tolerance and type 2 diabetes. One possible mediator of this improvement in insulin sensitivity is adiponectin.…”

Skeletal Muscle Metabolic Gene Expression Is Not Affected by Dichloroacetate-Mediated Modulation of Substrate Utilisation

“…However, the PPAR co-activator-1α, PGC1α, did increase significantly in CON, but not in DCA-treated subjects. PGC1α mRNA expression has previously been shown to increase during starvation [24], and with weight loss [25]. DCA may have had the effect of blocking any fasting-induced increase in PGC1α mRNA, through increasing carbohydrate utilisation, preventing the cell from sensing a physiological negative energy balance normally associated with saline infusions following an overnight fast.…”