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Adiponectin is an adipocyte-derived factor that plays a pivotal role in lipid and glucose metabolism. Recently, two types of adiponectin receptors (AdipoR1 and AdipoR2) were identified. We investigated whether exercise training (ET) or dietary restriction (DR) affects the expression of adiponectin receptors in skeletal muscle and liver, thereby improving glucose and lipid metabolism in KKAy mice. KKAy mice were subjected to 8 weeks of exercise training or food restriction. Following the experimental protocol, an intravenous glucose tolerance test and an intraperitoneal insulin tolerance test were performed in addition to the measurement of blood lipid and adiponectin concentrations. The mRNA levels of adiponectin, adiponectin receptors and genes that are putatively regulated by the adiponectin receptors were also analyzed. Both the 8-week exercise training and food restriction protocol improved insulin resistance in KKAy mice but did not alter plasma adiponectin concentration nor its mRNA expression. In comparison with C57BL/6 mice, AdipoR1 expression level was significantly decreased in skeletal muscle and AdipoR2 expression level was significantly increased in the liver in KKAy mice. After the 8-week experimental protocol, the expression level of AdipoR1 mRNA was approximately 1.8-fold greater in the skeletal muscle and 1.3-fold greater in the liver, and the level of AdipoR2 mRNA was 30% less in the liver of the ET group as compared with the control group. Additionally, in the ET group, mRNA expression of acyl coenzyme A-oxidase and carnitine palmitoyl transferase 1 (CPT1) was greater in the liver but not in skeletal muscle. In contrast, no significant changes were observed in the expression of genes encoding the adiponectin receptors in addition to other genes except for CPT1 in the DR group. These findings suggest that chronic exercise training affects the expression level of adiponectin receptors thereby improving insulin resistance in KKAy mice.

Vertical sleeve gastrectomy (VSG) is an effective surgery to treat obesity and diabetes. However, the direct effect of VSG on metabolic functions is not fully understood. We aimed to investigate if alterations in hypothalamic neurons were linked with perturbations in liver metabolism after VSG in an energy intake-controlled obese mouse model. C57BL/6 and hrNPY-GFP reporter mice received HFD for 12 weeks and were then divided into three groups: Sham (ad lib), Sham (pair-fed) with VSG and VSG. Food intake was measured daily, and blood glucose levels were measured before and after the study. Energy expenditure and body composition were determined. Serum parameters, liver lipid and glycogen contents were measured and gene/protein expression were analyzed. Hypothalamic POMC, AgRP/NPY and tyrosine hydroxylase-expressing neurons were counted. The following results were obtained. VSG reduced body weight gain and adiposity induced by HFD, increased energy expenditure independent of energy intake. Fed and fasted blood glucose levels were reduced in the VSG group. While serum active GLP-1 level was increased, the active ghrelin and triglycerides levels were decreased along with improved insulin resistance in VSG group. Liver lipid accumulation, glycogen content and gluconeogenic gene expression were reduced in the VSG group. In the hypothalamus, TH-expressing neuron population was decreased, and the POMC-expressing neuron population was increased in the VSG group. In conclusion, our data suggest that VSG improves metabolic symptoms by increasing energy expenditure and lowering lipid and glycogen contents in the liver. These physiological alterations are possibly related to changes in hypothalamic neuron populations.

Exercise plays a critical role in regulating glucose homeostasis and body weight. However, the mechanism of exercise on metabolic functions associated with the CNS has not been fully understood. C57BL6 male mice (n=45) were divided into three groups: normal chow diet, high-fat diet (HFD) treatment, and HFD along with voluntary running wheel exercise training for 12 weeks. Metabolic function was examined by the Comprehensive Lab Animal Monitoring System and magnetic resonance imaging; phenotypic analysis included measurements of body weight, food intake, glucose and insulin tolerance tests, as well as insulin and leptin sensitivity studies. By immunohistochemistry, the amount changes in the phosphorylation of signal transducer and activator of transcription 3, neuronal proliferative maker Ki67, apoptosis positive cells as well as pro-opiomelanocortin (POMC)-expressing neurons in the arcuate area of the hypothalamus was identified. We found that 12 weeks of voluntary exercise training partially reduced body weight gain and adiposity induced by an HFD. Insulin and leptin sensitivity were enhanced in the exercise training group verses the HFD group. Furthermore, the HFD-impaired POMC-expressing neuron is remarkably restored in the exercise training group. The restoration of POMC neuron number may be due to neuroprotective effects of exercise on POMC neurons, as evidenced by altered proliferation and apoptosis. In conclusion, our data suggest that voluntary exercise training improves metabolic symptoms induced by HFD, in part through protected POMC-expressing neuron from HFD and enhanced leptin signaling in the hypothalamus that regulates whole-body energy homeostasis.

Adiponectin secreted from adipose tissues plays a role in the regulation of energy homeostasis, food intake, and reproduction in the hypothalamus. We have previously demonstrated that adiponectin significantly inhibited GNRH secretion from GT1-7 hypothalamic GNRH neuron cells. In this study, we further investigated the effect of adiponectin on hypothalamic KISS1 gene transcription, which is the upstream signal of GNRH. We found that globular adiponectin (gAd) or AICAR, an artificial AMPK activator, decreased KISS1 mRNA transcription and promoter activity. Conversely, inhibition of AMPK by Compound C or AMPKα1-SiRNA augmented KISS1 mRNA transcription and promoter activity. Additionally, gAd and AICAR decreased the translocation of specificity protein-1 (SP1) from cytoplasm to nucleus; however, Compound C and AMPKα1-siRNA played an inverse role. Our experiments in vivo demonstrated that the expression of Kiss1 mRNA was stimulated twofold in the Compound C-treated rats and decreased about 60–70% in gAd- or AICAR-treated rats compared with control group. The numbers of kisspeptin immunopositive neurons in the arcuate nucleus region of Sprague Dawley rats mimicked the same trend seen in Ki ss 1 mRNA levels in animal groups with different treatments. In conclusion, our results provide the first evidence that adiponectin reduces Kiss1 gene transcription in GT1-7 cells through activation of AMPK and subsequently decreased translocation of SP1.

Recent evidence identifies a potent role for aerobic exercise to modulate the activity of hypothalamic neurons related to appetite; however, these studies have been primarily performed in male rodents. Since females have markedly different neuronal mechanisms regulating food intake, the current study aimed to determine the effects of acute treadmill exercise on hypothalamic neuron populations involved in regulating appetite in female mice. Mature, untrained female mice were exposed to acute sedentary, low- (10 m/min), moderate- (14 m/min), and high (18 m/min)-intensity treadmill exercise in a randomized crossover design. Mice were fasted 10 h before exercise, and food intake was monitored for 48 h after bouts. Immunohistochemical detection of cFOS was performed 3 h post-exercise to determine the changes in hypothalamic neuropeptide Y (NPY)/agouti-related peptide (AgRP), pro-opiomelanocortin (POMC), tyrosine hydroxylase (TH), and SIM1-expressing neuron activity concurrent with the changes in food intake. Additionally, stains for pSTAT3^tyr705 and pERK^{thr202/tyr204} were performed to detect exercise-mediated changes in intracellular signaling. Briefly, moderate- and high-intensity exercises increased 24-h food intake by 5.9 and 19%, respectively, while low-intensity exercise had no effects. Furthermore, increases in NPY/AgRP^ARC, SIM1^PVN, and TH neuron activity were observed 3 h after high-intensity exercise, with no effects on POMC^ARC neurons. While no effects of exercise on pERK^{thr202/tyr204} were observed, pSTAT3^tyr705 was elevated specifically in NPY/AgRP neurons 3 h post-exercise. Overall, aerobic exercise increased the activity of several appetite-stimulating neuron populations in the hypothalamus of female mice, which may provide insight into previously reported sexual dimorphisms in post-exercise feeding.

To address the roles of doublesex and mab-3-related transcription factor 1 (Dmrt1), forkhead transcription factor gene 2 (Foxl2), and aromatase in sex differentiation of Southern catfish, the cDNA sequences of these genes were isolated from the gonads. Dmrt1a and Dmrt1b were found to be expressed in the gonads, being higher in the testis. A low expression level of Dmrt1b was also detected in the intestine and kidney of the male. Foxl2 was found to be expressed extensively in the brain (B), pituitary (P), gill and gonads (G), with the highest level in the ovary, indicating the possible involvement of Foxl2 in the B–P–G axis. Cytochrome P450 (Cyp)19b was found to be expressed in the brain, spleen, and gonads, while Cyp19a was only expressed in the gonads and spleen. All-female Southern catfish fry were treated with fadrozole (F), tamoxifen (TAM), and 17β-estradiol (E₂) respectively, from 5 to 25 days after hatching (dah). The expression levels of these genes were measured at 65 dah. In the F-, TAM-, and FTAM-treated groups, Dmrt1a and Dmrt1b were up-regulated in the gonad, whereas Foxl2 and Cyp19a were down-regulated, while the expression of Cyp19b in the gonad remained unchanged. Furthermore, down-regulation of Foxl2 and Cyp19b was also detected in the brain. In the E₂-treated group, Dmrt1a and Dmrt1b were down-regulated to an undetectable level in the gonad, whereas Foxl2 and Cyp19b were up-regulated in the brain. Consistent with the observed changes in the expressions of these genes, 56, 70, and 80% sex-reversed male individuals were obtained in the F-, TAM-, and F + TAM-treated groups respectively. These results indicate the significant roles of Dmrt1, Foxl2, and Cyp19 in the sex differentiation of Southern catfish.

Vincamine, a monoterpenoid indole alkaloid extracted from the Madagascar periwinkle, is clinically used for the treatment of cardio-cerebrovascular diseases, while also treated as a dietary supplement with nootropic function. Given the neuronal protection of vincamine and the potency of β-cell amelioration in treating type 2 diabetes mellitus (T2DM), we investigated the potential of vincamine in protecting β-cells and ameliorating glucose homeostasis in vitro and in vivo. Interestingly, we found that vincamine could protect INS-832/13 cells function by regulating G-protein-coupled receptor 40 (GPR40)/cAMP/Ca²⁺/IRS2/PI3K/Akt signaling pathway, while increasing glucose-stimulated insulin secretion (GSIS) by modulating GPR40/cAMP/Ca²⁺/CaMKII pathway, which reveals a novel mechanism underlying GPR40-mediated cell protection and GSIS in INS-832/13 cells. Moreover, administration of vincamine effectively ameliorated glucose homeostasis in either HFD/STZ or db/db type 2 diabetic mice. To our knowledge, our current work might be the first report on vincamine targeting GPR40 and its potential in the treatment of T2DM.