Irisin is a cleaved and secreted fragment of fibronectin type III domain containing 5 (FNDC5), and contributes to the beneficial effects of exercise on metabolism. Here we report the therapeutical effects of FNDC5/irisin on metabolic derangements and insulin resistance in obesity, and show the lipolysis effect of irisin and its signal molecular mechanism. In obese mice, lentivirus mediated-FNDC5 overexpression enhanced energy expenditure, lipolysis and insulin sensitivity, and reduced hyperlipidemia, hyperglycemia, hyperinsulinism, blood pressure and norepinephrine levels; it increased hormone-sensitive lipase (HSL) expression and phosphorylation, and reduced perilipin level and adipocyte diameter in adipose tissues. Subcutaneous perfusion of irisin reduced hyperlipidemia and hyperglycemia, and improved insulin resistance. Either FNDC5 overexpression or irisin perfusion only induced a tendency toward a slight decrease in body weight in obese mice. In 3T3-L1 adipocytes, irisin enhanced basal lipolysis rather than isoproterenol-induced lipolysis, which were prevented by inhibition of adenylate cyclase or PKA; irisin increased the HSL and perilipin phosphorylation; it increased PKA activity, and cAMP and HSL mRNA levels, but reduced perilipin expression. These results indicate that FNDC5/irisin ameliorates glucose/lipid metabolic derangements and insulin resistance in obese mice, and enhances lipolysis via cAMP-PKA-HSL/perilipin pathway. FNDC5 or irisin can be taken as an effective therapeutic strategy for metabolic disorders.

It is known that sympathetic activity is significantly enhanced in obesity hypertension.1,2 Combined blockage of α-and β-receptors caused a greater decrease in blood pressure in obese hypertensive subjects than that in lean hypertensive subjects. 3 Autonomic ganglionic blockade induced a greater depressor response in obese rats than that in lean rats. 4 A greater depressor effect of ganglionic blocker was found in obese subjects than normal-weight subjects.5 Renal sympathetic denervation markedly attenuated sodium and water retention and hypertension in diet-induced obesity in dogs. 6 Excessive sympathetic activity plays a critical role in the pathogenesis and target organ complication of the obesity hypertension. [7][8][9] Muscle sympathetic nerve activity was more closely associated with the level of abdominal visceral fat than total fat mass or abdominal subcutaneous fat in obese humans.10 Fat in the abdominal viscera has a particularly strong effect on blood pressure.11 Central obesity is characterized by a greater sympathetic activation than that in peripheral obesity. 12Weight loss decreased the sympathetic activity in obese metabolic syndrome subjects. 13 These findings indicate that the increased abdominal visceral fat is an important factor contributing to sympathetic activation. The mechanisms involved in the sympathetic activation of obesity hypertension (OH) remain uncertain. However, some encouraging findings about the adipose afferent reflex (AAR) in our laboratory have shed light on revealing the neural mechanisms of sympathetic activation in OH. Injection of leptin into white adipose tissue (WAT) of rats increased the sympathetic outflow to the WAT, 14 brown adipose tissue, pancreas, liver, 15 and kidney. 16 We recently found that WAT injection of capsaicin, bradykinin, adenosine, or leptin increased renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in normal rats. WAT injection of capsaicin increased afferent nerve activity of the WAT and efferent nerve activity of both WAT and brown adipose tissue. Chemical stimulation of WAT-induced sympatho-excitatory reflex is called AAR.17 WAT denervation or chemical lesion of the neurons in paraventricular nucleus (PVN) abolished the AAR induced by chemical stimulation. These findings suggest that the AAR is involved in the regulation of sympathetic activity Abstract-We recently found that adipose afferent reflex (AAR) induced by chemical stimulation of white adipose tissue (WAT) increased sympathetic outflow and blood pressure in normal rats. The study was designed to test the hypothesis that AAR contributes to sympathetic activation in obesity hypertension. Male rats were fed with a control diet (12% kcal as fat) or high-fat diet (42% kcal as fat) for 12 weeks to induce obesity hypertension. Stimulation of WAT with capsaicin increased renal sympathetic nerve activity and mean arterial pressure. Both AAR and WAT afferent activity were enhanced in obesity hypertension (OH) compared with obesity nonhypertension (ON) and in ON compared...

Injection of leptin into white adipose tissue (WAT) increases sympathetic outflow. The present study was designed to determine the effects of capsaicin and other chemicals in WAT on the sympathetic outflow and blood pressure and the roles of WAT afferents and hypothalamic paraventricular nucleus (PVN) in the adipose afferent reflex (AAR). The AAR was induced by injection of capsaicin, bradykinin, adenosine, adenosine triphosphate (ATP), or leptin into inguinal WAT (iWAT) or retroperitoneal WAT (rWAT) in anesthetized rats. The iWAT injection of capsaicin increased the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) but not the heart rate. Bradykinin, adenosine, or leptin but not ATP in the iWAT caused similar effects to capsaicin on the RSNA and MAP. Intravenous, intramuscular, or intradermal injection of capsaicin had no significant effects on the RSNA and MAP. The effects of capsaicin in rWAT were similar to that in iWAT on the RSNA and MAP. Furthermore, injection of capsaicin into the iWAT increased the WAT afferent nerve activities, WAT efferent nerve activity, and brown adipose tissue efferent nerve activity. The iWAT denervation or chemical lesion of the PVN neurons with kainic acid abolished the AAR induced by the iWAT injection of capsaicin. These results indicate that the stimulation of iWAT afferents with capsaicin, bradykinin, adenosine, or leptin reflexly increases the RSNA and blood pressure. The iWAT afferents and the PVN are involved in the AAR induced by capsaicin in the iWAT.

Fibronectin type III domain-containing 5 (FNDC5) protein induces browning of subcutaneous fat and mediates the beneficial effects of exercise on metabolism. However, whether FNDC5 is associated with hepatic steatosis, autophagy, fatty acid oxidation (FAO), and lipogenesis remains unknown. Herein, we show the roles and mechanisms of FNDC5 in hepatic steatosis, autophagy, and lipid metabolism. Fasted FNDC5 mice exhibited severe steatosis, reduced autophagy, and FAO, and enhanced lipogenesis in the liver compared with wild-type mice. Energy deprivation-induced autophagy, FAO, and AMPK activity were attenuated in FNDC5 hepatocytes, which were restored by activating AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Inhibition of mammalian target of rapamycin (mTOR) complex 1 with rapamycin enhanced autophagy and FAO and attenuated lipogenesis and steatosis in FNDC5 livers. FNDC5 deficiency exacerbated hyperlipemia, hepatic FAO and autophagy impairment, hepatic lipogenesis, and lipid accumulation in obese mice. Exogenous FNDC5 stimulated autophagy and FAO gene expression in hepatocytes and repaired the attenuated autophagy and palmitate-induced steatosis in FNDC5 hepatocytes. FNDC5 overexpression prevented hyperlipemia, hepatic FAO and autophagy impairment, hepatic lipogenesis, and lipid accumulation in obese mice. These results indicate that FNDC5 deficiency impairs autophagy and FAO and enhances lipogenesis via the AMPK/mTOR pathway. FNDC5 deficiency aggravates whereas FNDC5 overexpression prevents the HFD-induced hyperlipemia, hepatic lipid accumulation, and impaired FAO and autophagy in the liver.

The aim of this study was to determine whether reactive oxygen species (ROS) in the paraventricular nucleus (PVN) mediate both the cardiac sympathetic afferent reflex (CSAR) and angiotensin II-induced CSAR enhancement in chronic heart failure (CHF) rats. CSAR was evaluated from the responses of renal sympathetic nerve activity (RSNA) to epicardial application of bradykinin. In both CHF and shamoperated rats, PVN microinjection of the superoxide anion scavengers tempol or tiron almost abolished the CSAR, but the superoxide dismutase inhibitor DETC potentiated the CSAR. PVN pretreatment with tempol or tiron abolished, whereas DETC augmented, the angiotensin II-induced CSAR enhancement. In CHF rats, superoxide anion and malondialdehyde (MDA) levels in the PVN were increased, but were normalized by the AT 1 receptor antagonist losartan. PVN microinjection of tempol decreased superoxide anion and MDA levels, but epicardial application of bradykinin or PVN microinjection of angiotensin II increased superoxide anion and MDA to higher levels in CHF rats than in sham-operated rats. These results indicate that ROS in the PVN mediates the CSAR and the effect of angiotensin II in the PVN on the CSAR in both CHF and sham-operated rats. Increased ROS in the PVN are involved in the enhanced CSAR in CHF.