Upregulated meteorin-like (Metrnl) protein in peripheral tissues because of exercise-induced increases in intramuscular Metrnl may effectively alleviate obesity by improving metabolism in whole-body tissues. The objective was to analyse the effects of regular treadmill exercise on Metrnl levels in muscle and peripheral tissues of chronic high-fat diet- (HFD-) induced obese mice. Forty-eight-week-old male C57BL/6 mice were first divided equally into normal-diet (CO) and high-fat diet (HF) groups. Following 16 weeks of a HFD, each group was again split equally into control (CO, HF) and training groups (COT, HFT). The HFT group expressed significantly higher phospho-AMP-activated protein kinase (AMPK), AMPK activity, and peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α) in muscle tissue than the HF group (p<0.05). Similar to muscle energy sensing network protein levels, the HFT group also expressed significantly higher muscle, plasma, and adipose tissue Metrnl (p<0.05). Moreover, regular exercise increased acyl-CoA oxidase 1 (ACOX-1) and monoglyceride lipase (MGL) expression in adipose tissue (p<0.05) and significantly decreased abdominal fat mass (p<0.05). This study suggests that exercise-induced muscle Metrnl effectively reduces fat accumulation through the increase of Metrnl in adipose tissue, which may be a therapeutic target for chronic obesity.

This study aimed to analyze the effect of exercise and/or dietary change on improvement of non-alcoholic fatty liver disease (NAFLD) in chronic high-fat diet (HFD)-induced obese mice. Forty male C57BL/6 (8 weeks old) mice were divided into normal diet (CO, n = 8) and high-fat diet (HF, n = 32) groups. The HF group was fed with 60% fat chow for 16 weeks to induce obesity. After the obesity induction period, the HF group was subdivided into HFD + sedentary (n = 8), HFD + training (HFT, n = 8), dietary change to normal-diet + sedentary (HFND, n = 8), and dietary change to normal-diet + training (HFNDT, n = 8) groups, and the mice in the training groups underwent treadmill training for 8 weeks, 5 times per week, 40 min per day. A 24-week HFD induced increase of cannabinoid-1 receptor (CB1), fatty acid synthase (FAS), and AMP-activated protein kinase (AMPK) protein expressions (p < 0.05) and decrease of p-AMPK and carnitine palmitoyltransferase1 (CPT1) protein expressions (P < 0.05), resulting in increased liver fat accumulation. Treatment of exercise with dietary change and dietary change alone decreased CB1 and AMPK protein expressions with increased p-AMPK and CPT1 protein expressions (P < 0.05), leading to decreased body weight and liver fat (P < 0.05). The CB1 and FAS protein expressions in the HFT group were still higher than those in the CO group (P < 0.05), but the p-AMPK and CPT1 protein expressions were higher than those in the HF group (P < 0.05). Moreover, improved glucose tolerance and decreased liver fat were confirmed, although treatment of exercise alone had no effect on weight loss compared to pre-exercise. Even in the case of obesity induced by chronic HFD, exercise and/or dietary interventions have preventive and therapeutic effects on fat accumulation in the liver, resulting from upregulations of lipolytic factors. Therefore, the results of this study suggested that treatment of exercise alone without dietary change also leads to improvement of NAFLD and glucose tolerance without weight loss benefits.

Increased intramuscular peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) with exercise directly or indirectly affects other tissues, but the effector pathway of PGC-1α has not been clearly elucidated. The purpose of this study was to investigate the effect of exercise and/or dietary change on the protein levels of the soleus muscle energy-sensing network and meteorin-like (Metrnl), and additionally to analyze the detraining and retraining effects in high-fat diet (HFD)-induced obese mice. One hundred male C57BL/6 mice were divided into normal-diet + sedentary (CO, n = 20) and HFD + sedentary (HF, n = 80) groups, and obesity was induced in the HF group through consumption of a 45% HFD for 6 weeks. The HF group was subdivided into HF only (n = 20), HF + training (HFT, n = 20), dietary change + sedentary (HFND, n = 20), and HFND + training (HFNDT, n = 20) groups, and the mice in the training groups underwent a treadmill training for 8 weeks, 5 times per week, 40 min per day. The HFT and HFNDT groups underwent 8-week training, 8-week detraining, and 4-week retraining. An 8-week training was effective in increasing the protein levels of soleus muscle AMP-activated protein kinase (AMPK), PGC-1α, and plasma Metrnl in the obese mice (P < 0.05). Moreover, exercise in obesity reduced body weight (P < 0.05), and exercise with dietary conversion was effective in reducing body weight (P < 0.05) and fat mass (P < 0.05) after 8-week training. 8-week detraining restored the increased protein level to the pre-exercise state, but, the previous exercise effect in body weight and fat mass (P < 0.05) of the HFNDT group remained until the end of 4-week detraining. 4-week retraining was effective in increasing the protein levels of soleus muscle AMPK, PGC-1α, blood Metrnl (P < 0.05), and reducing in body weight (P < 0.05) and fat mass (P < 0.05), when retraining with dietary change. The results of this study suggest that regular exercise is indispensable to reduce body weight and fat mass through upregulation of the muscle energy-sensing network and Metrnl protein levels, and retraining with dietary change is necessary to obtain the retraining effects more quickly.

Free fatty acids (FFAs), which are elevated with metabolic syndrome, are considered the principal offender exerting lipotoxicity. Few previous studies have reported a causal relationship between FFAs and osteoarthritis pathogenesis. However, the molecular mechanism by which FFAs exert lipotoxicity and induce osteoarthritis remains largely unknown. We here observed that oleate at the usual clinical range does not exert lipotoxicity while oleate at high pathological ranges exerted lipotoxicity through apoptosis in articular chondrocytes. By investigating the differential effect of oleate at toxic and nontoxic concentrations, we revealed that lipid droplet (LD) accumulation confers articular chondrocytes, the resistance to lipotoxicity. Using high fat diet-induced osteoarthritis models and articular chondrocytes treated with oleate alone or oleate plus palmitate, we demonstrated that articular chondrocytes gain resistance to lipotoxicity through protein kinase casein kinase 2 (PKCK2)—six-transmembrane protein of prostate 2 (STAMP2)—and fat-specific protein 27 (FSP27)-mediated LD accumulation. We further observed that the exertion of FFAs-induced lipotoxicity was correlated with the increased concentration of cellular FFAs freed from LDs, whether FFAs are saturated or not. In conclusion, PKCK2/STAMP2/FSP27-mediated sequestration of FFAs in LD rescues osteoarthritic chondrocytes. PKCK2/STAMP2/FSP27 should be considered for interventions against metabolic OA.

The purpose of this study was to investigate the effect of regular treadmill exercise on the mRNA expressions of myokines and angiogenesis factors in the skeletal muscle of obese rats. Thirty two male Sprague-Dawley rats (4weeks old) were divided into the CO (control) and HF (high fat diet) groups. Obesity was induced in the HF group by consumption of 45% high-fat diet for 15 weeks. These groups were further subdivided into training groups (COT and HFT); the training groups conducted moderate intensity treadmill training for 8 weeks. Soleus muscles were excised and analyzed by real-time quantitative PCR. mRNA expression of myokines, such as PGC-1α, IL-6, and IL-15, in the COT and HFT groups (which conducted regular exercise), were higher as compared with the CO and HF groups (p < 0.05). Also, the levels in the HF group were significantly lower when compared with CO group (p < 0.05). Expression of angiogenesis mRNA, namely mTOR, VEGF, and FLT1, were significantly lower in the HF group, as compared to the CO group (p < 0.05). In addition, COT group had a higher expression of mTORC1, mTORC2, VEGF and FLT mRNA, than the CO group (p < 0.05); the HFT group also had higher expressions of mTOR, VEGF and FLT1 mRNA than the HF group (p < 0.05). These results indicate that mRNA expression of myokines was increased through the activity of muscle contraction, and it also promoted the mRNA expression of angiogenesis due to activation of mTOR. Thus, we conclude that not only under normal health conditions, but in obesity and excess nutritional circumstances also, regular exercise seems to act positively on the glycemic control and insulin sensitivity through the angiogenesis signaling pathway.