BDNF produced by skeletal muscle in female mice enables switching of fuel sources during fasting.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases with limited treatment options. Moreover, its prevalence is doubled in type 2 diabetes mellitus (T2DM). Kaempferol (KAP) is a flavonoid compound that has been suggested to have beneficial effects on NAFLD, but studies on the mechanism are lacking, especially in the diabetic state. Herein, we investigated the effect of KAP on NAFLD associated with T2DM and its underlying mechanism in vitro and in vivo. The results of in vitro studies indicated that KAP treatment (10^-8-10^-6 M) significantly reduced lipid accumulation in oleic acid-induced HepG2 cells. Moreover, in the T2DM animal model of db/db mice, we confirmed that KAP (50 mg/kg) significantly reduced lipid accumulation and improved liver injury. Mechanistic studies in vitro and in vivo showed that Sirtuin 1 (Sirt1)/AMP-activated protein kinase (AMPK) signal was involved in KAP regulation of hepatic lipid accumulation. KAP treatment activated Sirt1 and AMPK, upregulated the levels of fatty acid oxidation-related protein proliferator activated receptor gamma coactivator 1α (PGC1α); and downregulated lipid synthesis-related proteins, including acetyl-coA carboxylase (ACC), fatty acid synthase (FASN), and sterol regulatory element-binding protein 1 (SREBP1). Furthermore, the curative effect of KAP on lipid accumulation was abolished by siRNA-mediated knockdown of either Sirt1 or AMPK. Collectively, these findings suggest that KAP may be a potential therapeutic agent for NAFLD associated with T2DM by regulating hepatic lipid accumulation through activation of Sirt1/AMPK signaling.

Puerarin is an isoflavonoid extracted from Pueraria lobate with extensive pharmacological effects in traditional Chinese medicine. The evidence implicates that puerarin mitigates hyperglycemia and various relevant complications. Here, the effect of puerarin on skeletal muscle wasting induced by type 1 diabetes (T1D) was explored. Streptozotocin (STZ)-induced T1D male Sprague Dawley (SD) rats were used in this study. Muscle strength, weight and size were measured. L6 rat skeletal muscle cells were applied for in vitro study. Our results showed that eight-week oral puerarin administration (100 mg/kg) increased muscle strengths and weights accompanied by enhanced skeletal muscle cross-sectional areas in diabetic rats. Simultaneously, puerarin also reduced expressions of several muscle wasting marker genes including F-box only protein 32 (Atrogin-1) and muscle-specific RING-finger 1 (Murf-1) in diabetic group both in vitro and in vivo. Transformation from type I fibers (slow muscle) to type II fibers (fast muscle) were also observed under puerarin administration in diabetic rats. Puerarin promoted Akt/mTOR while inhibited LC3/p62 signaling pathway in skeletal muscle cells. In conclusion, our study showed that puerarin mitigated skeletal muscle wasting in T1D rats and closely related with Akt/mTOR activation and autophagy inhibition. Whether this effect in murine applies to humans remains to be determined.

Salvianolic acid A (SalA) is one of the main efficacious, water-soluble constituents of Salvia miltiorrhiza Bunge. This study investigated the protective effects of SalA on peripheral nerve in diabetic rats. Administration of SalA (0.3, 1 and 3 mg/kg, ig) was started from the 5th week after strepotozotocin (STZ60 mg/kg) intraperitoneal injection and continued for 8 weeks. Paw withdrawal mechanical threshold (PWMT) and motor nerve conduction velocity (MNCV) were used to assess peripheral nerve function. The western blot methods were employed to test the expression levels of serine-threonine liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α), silent information regulator protein3 (sirtuin 3/Sirt3) and neuronal nitric oxide synthase (nNOS) in sciatic nerve. Results showed that SalA administration could increase PWMT and MNCV in diabetic rats; reduce the deterioration of sciatic nerve pathology; increase AMPK phosphorylation level, up-regulate PGC-1α, Sirt3 and nNOS expression, but had no influence on LKB1. These results suggest that SalA has protective effects against diabetic neuropathy. The beneficial effects of SalA on peripheral nerve function in diabetic rats might be attributed to improvements in glucose metabolism through regulation of the AMPK-PGC1α-Sirt3 axis.

Post-exercise recovery is essential to resolve metabolic perturbations and promote long-term cellular remodeling in response to exercise. Here, we report that muscle-generated brain-derived neurotrophic factor (BDNF) elicits post-exercise recovery and metabolic reprogramming in skeletal muscle. BDNF increased the post-exercise expression of the gene encoding PPARδ (peroxisome proliferator–activated receptor δ), a transcription factor that is a master regulator of lipid metabolism. After exercise, mice with muscle-specific Bdnf knockout ( MBKO ) exhibited impairments in PPARδ-regulated metabolic gene expression, decreased intramuscular lipid content, reduced β-oxidation, and dysregulated mitochondrial dynamics. Moreover, MBKO mice required a longer period to recover from a bout of exercise and did not show increases in exercise-induced endurance capacity. Feeding naïve mice with the bioavailable BDNF mimetic 7,8-dihydroxyflavone resulted in effects that mimicked exercise-induced adaptations, including improved exercise capacity. Together, our findings reveal that BDNF is an essential myokine for exercise-induced metabolic recovery and remodeling in skeletal muscle.