There are only a limited number of reports on the role of PGC- 1a in the regulation of autophagy. A positive correlation between an increase in PGC-1a and autophagy has been shown in lipopolysaccharide-treated neonatal rat cardiomyocytes. Similarly, activation of PPAR-c induced autophagy in breast cancer cells through upregulation of the HIF-1a protein and BNIP3. On the other hand, PGC-1a was shown to inhibit autophagic/lysosomal protein degradation in myotubes and to suppress autophagy in muscles in aged PGC-1a transgenic mice. In our system PGC-1a clearly induced autophagy in both control and KO mice. Enzalutamide Another finding related to the function of PGC-1a itself is a significant increase in the number of lysosomes which became obvious because of the KO background. Thus, our data suggest that PGC-1a is a regulator not only of mitochondrial but also of lysosomal and autophagosomal biogenesis. A combination of enhanced lysosomal capacity and increased production of autophagosomes without autophagic buildup resulted in more efficient disposal of autophagic cargo, in particular Ub-proteins, in tgKO than in KO mice. Clearance of potentially toxic Ub-substrates is a major problem in neurodegenerative diseases, and the induction of autophagy has emerged as a therapeutic approach designed to rid the cells of these abnormal protein aggregates ]. Our data on the upregulation of autophagy by PGC-1a suggest that pharmacological activation of this molecule might have a therapeutic benefit for a range of neurodegenerative diseases caused by the accumulation of such aggregates. Finally, the failure of ERT in tgKO mice may be due to very high, non-physiologic levels of PGC-1a transgene expression, which even exceed the endogenous levels of PGC-1a in type I soleus muscle.. It has been shown that modest PGC-1a expression in skeletal muscle increased insulin PI-103 sensitivity whereas excessive PGC-1a expression in transgenic mice rendered skeletal muscle resistant to insulin. A moderate increase in PGC-1a can be achieved by exercise as demonstrated in humans and in rats. Other routes of fiber type conversion may be more successful. It has recently been shown that the expression of the myosin intronic microRNA in skeletal muscle powerfully induced the conversion from fast to a slower myofiber type. Thus, the disappointing outcome of therapy in tgKO cannot be viewed as a final verdict on the merits of fiber type conversion. Leptin, a 16-kDa protein produced mainly in adipose tissue and secreted into the bloodstream, plays an important role in regulating body weight, metabolism and reproductive function. Circulating leptin levels are highly correlated with white adipose tissue mass. The lack of leptin action causes a disruption in energy balance with hyperphagia and decreased energy expenditure, leading to morbid obesity and development of type 2 diabetes.