Effects of adiponectin on skeletal and cardiac muscle cell metabolism

Adiponectin regulates glucose and fat metabolism and controls energy homeostasis In skeletal muscle and heart. This thesis investigated: Study 1: the effects of hyperglycemia or hyperinsulinemia on adiponectin's metabolic functions in muscle cells; Study 2: the signalling and functional crosstalk between adiponectin and leptin in muscle cells; Study 3: the effects of adiponectin on myocardial metabolism; and Study 4: metabolic responses to fAd or tAd in muscle cells.;In study 2, leptin inhibited the metabolic effects of fAd and gAd. Leptin decreased the expression of AdipoR1 and AdipoR2 and attenuated adiponectin signalling. The enhancing effect of fAd on insulin signaling was also attenuated by leptin. Thus, leptin attenuated the direct metabolic and insulin-sensitising effects of adiponectin.;In study 3, adiponectin activated lipoprotein lipase and stimulated fatty acid uptake and oxidation via mechanisms that require activation of AMPK, ACC, translocation of CD36 and APPL1 interaction with downstream molecules in primary rat cardiomyocytes. In isolated working mouse hearts adiponectin increased palmitate oxidation and proportionately increased myocardial oxygen consumption and cardiac hydraulic work thereby maintaining cardiac efficiency, while reducing glucose metabolism. Thus, adiponectin increases myocardial FA utilization without limiting cardiac efficiency via multiple mechanisms that are mediated in part by APPL1-dependent activation of AMPK.;In study 4, tAd stimulated glucose uptake and fatty acid uptake that may be mediated by activation of Akt while fAd exerted these effects likely via AMPK. fAd and tAd stimulated fatty acid oxidation at 24h likely via an AMPK-independent pathway. These findings suggest functional and signalling specificity of different forms of adiponectin.;In study 1, hyperglycemia and hyperinsulinemia both decreased AdipoR1 expression by 50% which may cause gAd resistance and lead to attenuated gAd signalling and metabolic functions. However, hyperinsulinemia increased fAd sensitivity which may be attributed to a ∼ 3-fold increase of AdipoR2 expression. These results suggest that both hyperglycemia and hyperinsulinemia cause gAd resistance in rat skeletal muscle cells. However, hyperinsulinemia enhanced fAd sensitivity in these cells.;Collectively, these results provided new insight into adiponectin signaling and function in skeletal muscle and heart as well as sensitivity of skeletal muscle metabolism under pathological conditions to adiponectin.