Sexual dimorphism has been found in mitochondrial features of skeletal muscle, with female rats showing greater mitochondrial mass and function compared with males. Adiponectin is an insulin-sensitizing adipokine whose expression has been related to mitochondrial function and that is also expressed in skeletal muscle, where it exerts local metabolic effects. The aim of this research was to elucidate the role of sex hormones in modulation of mitochondrial function, as well as its relationship with adiponectin production in rat skeletal muscle. Anin vivostudy with ovariectomized Wistar rats receiving or not receiving 17β-estradiol (E₂) (10 μg/kg per 48 h for 4 weeks) was carried out, in parallel with an assay of cultured myotubes (L6E9) treated with E₂(10 nM), progesterone (Pg; 1 μM), or testosterone (1 μM). E₂upregulated the markers of mitochondrial biogenesis and dynamics, and also of mitochondrial function in skeletal muscle and L6E9. Althoughin vivoE₂supplementation only partially restored the decreased adiponectin expression levels induced by ovariectomy, these were enhanced by E₂and Pg treatment in cultured myotubes, whereas testosterone showed no effects. Adiponectin receptor 1 expression was increased by E₂treatment, bothin vivoandin vitro, but testosterone decreased it. In conclusion, our results are in agreement with the sexual dimorphism previously reported in skeletal muscle mitochondrial function and indicate E₂to be its main effector, as it enhances mitochondrial function and diminishes oxidative stress. Moreover, our data support the idea of the existence of a link between mitochondrial function and adiponectin expression in skeletal muscle, which could be modulated by sex hormones.

Muscle resistance to insulin plays a key role in the metabolic dysregulation associated to obesity. A pro-inflammatory and pro-oxidant status has been proposed to be the link between dietary obesity and insulin resistance. Given the gender differences previously found in mitochondrial function and oxidative stress, the aim of the present study was to investigate whether this gender dimorphism leads to differences in the development of high-fat-diet-induced insulin resistance in rat skeletal muscle. Male and female rats of 15 months of age were fed with a high-fat-diet (32% fat) for 14 weeks. Control male rats showed a more marked insulin resistance status compared to females, as indicated by the glucose tolerance curve profile and the serum insulin, resistin and adiponectin levels. High-fat-diet feeding induced an excess of body weight of 16.2% in males and 38.4% in females, an increase in both muscle mitochondrial hydrogen peroxide production and in oxidative damage, together with a decrease in the Mn-superoxide dismutase activity in both genders. However, high-fat-diet fed female rats showed a less marked insulin resistance profile than males, higher mitochondrial oxygen consumption and cytochrome c oxidase activity, and a better capacity to counteract the oxidative-stress-dependent insulin resistance through an overexpression of both muscle UCP3 and GLUT4 proteins. These results point to a gender dimorphism in the insulin resistance status and in the response of skeletal muscle to high-fat-diet feeding which could be related to a more detrimental effect of age in male rats.

Mitochondrial biogenesis includes both mitochondrial proliferation and differentiation and its regulation under different physiological conditions is not clear. Given the sexual dimorphism previously found in mitochondrial function, the aim of this study was to investigate the gender-dependent effect of chronic high-fat-diet (HFD) feeding on rat liver mitochondrial function and biogenesis. Ten-week old male and female rats were fed a HFD (26% fat) or a control diet (2.9% fat) for 26 weeks. Mitochondrial morphology was studied. Mitochondrial DNA and protein content, hydrogen peroxide production, oxidative capacity, antioxidant defenses, as well as markers of oxidative damage and mitochondrial biogenesis were analyzed. Female rats showed higher levels of mitochondrial protein and an enhanced oxidative capacity per mitochondrion than males. In both genders, HFD feeding increased mtDNA content and decreased mitochondrial differentiation markers. In comparison to male rats, females show higher oxidative capacity as a consequence of their greater mitochondrial differentiation under both control and obese status. In response to HFD feeding, the oxidative capacity of the whole mitochondrial population is maintained in both genders. This is obtained by means of an enhancement of mitochondrial proliferation, which counteracts the diet-induced impairment of the function of each mitochondrion.

Sexual dimorphism has been found in both mitochondrial functionality and adiponectin expression in white adipose tissue, with female rats presenting more functional mitochondria than males and greater adiponectin expression. However, little is known about the role of sex hormones in this dimorphism. The aim was to elucidate the role of sex hormones in mitochondrial biogenesis and dynamics and in adiponectin synthesis in white adipocytes, and also to provide new evidence of the link between these processes. 3T3-L1 preadipocytes were differentiated and treated either with 17-β estradiol (E₂; 10 nM), progesterone (Pg), testosterone (1 μM both), or a combination of Pg or testosterone with flutamide (FLT; 10 μM) or E₂(1 μM). The markers of mitochondrial biogenesis and dynamics and adiponectin expression were analyzed. E₂induced mitochondrial proliferation and differentiation in 3T3-L1, although testosterone showed opposite effects. Pg treatment stimulated proliferation but impaired differentiation. In concerns mitochondrial dynamics, these hormones promoted fusion over fission. FLT treatment indicated that Pg elicits its effects on mitochondrial dynamics through the androgen receptor. E₂coadministration with testosterone or Pg reversed its effects. In conclusion, our results show that E₂induces stimulation of mitochondrial biogenesis in white adipocytesin vitro, especially in situations that imply an impairment of mitochondrial function, whereas testosterone would have opposite effects. Moreover, testosterone and Pg alter mitochondrial dynamics by promoting fusion over fission, while E₂stimulates both processes. All these alterations run in parallel with changes in adiponectin expression, thus suggesting the existence of a link between mitochondrial biogenesis and dynamics and adiponectin synthesis in white adipocytes.