Time-restricted feeding prevents metabolic diseases through the regulation of galanin/GALR1 expression in the hypothalamus of mice.

PURPOSE: Time-restricted feeding (TRF) reverses obesity and insulin resistance, yet the central mechanisms underlying its beneficial effects are not fully understood. Recent studies suggest a critical role of hypothalamic galanin and its receptors in the regulation of energy balance. It is yet unclear whether TRF could regulate the expression of galanin and its receptors in the hypothalamus of mice fed a high-fat diet. METHODS: To test this effect, we subjected mice to either ad lib or TRF of a high-fat diet for 8 h per day. After 4 weeks, galanin and many neuropeptides associated with the function of metabolism were examined. RESULTS: The present findings showed that mice under TRF consume equivalent calories from a high-fat diet as those with ad lib access, yet are protected against obesity and have improved glucose metabolism. Plasma galanin, orexin A, irisin and adropin levels were significantly reversed by TRF regimen. Besides, TRF regimen reversed the progression of metabolic disorders in mice by increasing GLUT4 and PGC-1α expression in skeletal muscles. Moreover, the levels of galanin and GALR1 expression were severely diminished in the hypothalamus of the TRF mice, whereas GALR2 was highly expressed. CONCLUSIONS: TRF diminished galanin and GALR1 expression, and increased GALR2 expression in the hypothalamus of mice fed a high-fat diet. The current studies provide additional evidence that TRF is effective in improving HFD-induced hyperglycemia and insulin resistance in mice, and this effect could be associated with TRF-induced changes of the galanin systems in the hypothalamus. LEVEL OF EVIDENCE: No level of evidence, animal studies.

Galanin peptide family regulation of glucose metabolism.

Recent preclinical and clinical studies have indicated that the galanin peptide family may regulate glucose metabolism and alleviate insulin resistance, which diminishes the probability of type 2 diabetes mellitus. The galanin was discovered in 1983 as a gut-derived peptide hormone. Subsequently, galanin peptide family was found to exert a series of metabolic effects, including the regulation of gut motility, body weight and glucose metabolism. The galanin peptide family in modulating glucose metabolism received recently increasing recognition because pharmacological activiation of galanin signaling might be of therapeutic value to improve insuin resistance and type 2 diabetes mellitus. To date, however, few papers have summarized the role of the galanin peptide family in modulating glucose metabolism and insulin resistance. In this review we summarize the metabolic effect of galanin peptide family and highlight its glucoregulatory action and discuss the pharmacological value of galanin pathway activiation for the treatment of glucose intolerance and type 2 diabetes mellitus.

Effect of Baicalein on GLUT4 Translocation in Adipocytes of Diet-Induced Obese Mice.

BACKGROUND/AIMS: Although baicalein has been shown to increase insulin sensitivity in liver of mice, there is no literature available about the effect of baicalein on glucose transporter 4 (GLUT4) translocation from intracellular membrane pools to plasma membranes in adipocytes of diet-induced obese mice. METHODS: In the present study, the obese model was induced in mice fed a high fat diet (20% carbohydrates, 21% protein and 59% fat) for 16 weeks. The diet-induced obese mice were given 20mg/kg baicalein intraperitoneally (i.p.) once a day for 21 days. The plasma insulin was measured by enzyme-linked immunosorbent assay. Fasting blood glucose and insulin resistance indexes were measured by glucose tolerance test (GTT). The expression levels of PGC-1α, UCP1, GLUT4, PPARγ, pP38MAPK, pERK and pAKT in adipocytes were determined by quantitative real-time polymerase chain reaction and western blotting. RESULTS: The present findings showed that administration of baicalein decreased pP38MAPK, pERK and PPARγ levels, but enhanced pAKT, PGC-1α and UCP1 contents as well as GLUT4 expression in adipocytes, and reversed high fat diet-induced glucose intolerance, hyperglycemia and insulin resistance in diet-induced obese mice. Moreover, baicalein treatment increased GLUT4 concentration in plasma membranes of adipocytes, i.e. baicalein may prevent insulin resistance through the GLUT4 translocation from intracellular membrane compartments to plasma membranes in adipocytes. CONCLUSION: These results suggest that baicalein is a powerful and promising agent for treatment of obesity and insulin resistance via Akt/GLUT4 pathway.

Akt2-Dependent Beneficial Effect of Galanin on Insulin-Induced Glucose Uptake in Adipocytes of Diabetic Rats.

BACKGROUND/AIMS: Glucose uptake occurs via the activation of an insulin-signaling cascade, resulting in the translocation of glucose transporter 4 (GLUT4) to the plasma membrane of adipocytes and myocytes. Recent research found that galanin could boost insulin-induced glucose uptake. This study aimed to explore whether activation of Akt2 mediates the beneficial effects of galanin on insulin-induced glucose uptake in the adipocytes of diabetic rats. METHOD: In this experiment, insulin, galanin and MK-2206, an Akt inhibitor, were injected individually or in combination into diabetic rats once a day for ten days. Then, glucose uptake and pAkt2 and its downstream proteins were examined in adipocytes. RESULTS: Administration of galanin significantly enhanced insulin-induced 2-Deoxy-D-[3H]glucose uptake; GLUT4 and vesicle-associated membrane protein 2 contents in plasma membranes; and pAkt2Thr308/Ser473 and Akt2 mRNA expression levels in adipocytes. In addition, Akt2 downstream proteins including phosphorylated AS160 were increased, but the levels of phosphorylated forkhead box O1 and glycogen synthase kinase-3ß were reduced. Treatment with MK-2206 may block the beneficial effects of galanin on these insulin-induced events. CONCLUSIONS: The results of this study suggest that phosphorylation of Akt2 mediates the beneficial effects of galanin on insulin-induced glucose uptake in the adipocytes of diabetic rats.

Beneficial effects of neuropeptide galanin on reinstatement of exercise-induced somatic and psychological trauma.

Galanin is a versatile neuropeptide that is distinctly upregulated by exercise in exercise-related tissues. Although benefits from exercise-induced upregulation of this peptide have been identified, many issues require additional exploration. This Review summarizes the information currently available on the relationship between galanin and exercise-induced physical and psychological damage. On the one hand, body movement, exercise damage, and exercise-induced stress and pain significantly increase local and circulatory galanin levels. On the other hand, galanin plays an exercise-protective role to inhibit the flexor reflex and prevent excessive movement of skeletal muscles through enhancing response threshold and reducing acetylcholine release. Additionally, elevated galanin levels can boost repair of the exercise-induced damage in exercise-related tissues, including peripheral nerve, skeletal muscle, blood vessel, skin, bone, articulation, and ligament. Moreover, elevated galanin levels may serve as effective signals to buffer sport-induced stress and pain via inhibiting nociceptive signal transmission and enhancing pain threshold. This Review deepens our understanding of the profitable roles of galanin in exercise protection, exercise injury repair, and exercise-induced stress and pain. Galanin and its agonists may be used to develop a novel preventive and therapeutic strategy to prevent and treat exercise-induced somatic and psychological trauma. © 2016 Wiley Periodicals, Inc.

Plasma orexin-A level associated with physical activity in obese people.

OBJECTIVE: To measure the amount of physical activity (PA) among obese adults, investigate the association between plasma orexin-A level and PA patterns, and explore the effect of orexin on the prevention and control of obesity. METHODS: Interviews were conducted in 218 participants (106 obese; 73 overweight; and 39 normal) who ranged in age between 18 and 70 years using a survey that included sociodemographic variables. The International Physical Activity Questionnaire (IPAQ-long version) was used to measure PA. A total of 178 participants agreed to submit blood sample collections, and plasma orexin-A content was measured by ELISA testing. RESULTS: The average level of orexin-A was 85.34 ± 42.85 ng/L in the obese group, 97.38 ± 36.72 ng/L in the overweight group, and 106.56 ± 52.09 ng/L in the control group, which was significantly different (P = 0.03). The concentration of plasma orexin-A correlated with the total PA (P = 0.000), moderate PA (obese = 0.007; overweight: P = 0.000; control: P = 0.000), and walking PA (P = 0.000) in all three groups. Working and domestic PAs were significantly associated with the plasma orexin-A level (P < 0.0001). CONCLUSIONS: The plasma orexin-A level was associated with PA in obese and overweight people, including many aspects of daily life, such as working, domestic work, and walking especially.

Baicalin suppresses macrophage JNK-mediated adipose tissue inflammation to mitigate insulin resistance in obesity.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix scutellariae (the root of Scutellaria baicalensis Georgi) is a traditional Chinese medicine (TCM) used to treat a wide range of inflammation-related diseases, such as obesity, diabetes, diabetic kidney disease, and COVID-19-associated inflammatory states in the lung and kidney. Baicalin is the major anti-inflammatory component of Radix scutellariae and has shown the potential to inhibit inflammation in metabolic disorders. In this study, we explored the ability and underlying mechanisms of baicalin to modulate the macrophage to mitigate insulin resistance in obesity. MATERIALS AND METHODS: Obese mice were administered baicalin (50 mg/kg/day) intraperitoneally for 3 weeks. RAW264.7 and BMDM cells were stimulated with LPS and treated with baicalin for 24 h, while 3T3-L1 and primary white adipocytes were treated with the supernatants from baicalin-treated RAW264.7 cells for 24 h. RESULTS: The results showed that baicalin significantly improved glucose and insulin tolerance as well as decreased fat and adipose tissue macrophage levels in obese mice. Besides, baicalin significantly reduced serum and adipose tissue IL-1ß, TNF-α and IL-6 levels in obese mice, as well as suppressed LPS-induced IL-1ß, TNF-α and IL-6 expression and release in macrophages. Furthermore, treatment with the supernatant from baicalin-treated RAW264.7 cells increased the levels of PGC-1α, SIRT1, p-IRS-1 and p-AKT in adipocytes. Moreover, baicalin treatment dramatically downregulated macrophage p-p38, p-JNK, and Ac-p65Lys310 levels while increasing SIRT1 both in vivo and in vitro. Importantly, JNK inhibitor SP600125 blocked most of the effects of baicalin on SIRT1, Ac-p65Lys310 and pro-inflammatory factors in macrophages. CONCLUSION: Therefore, these results demonstrated for the first time that baicalin exerts its anti-inflammatory effects in obese adipose tissue macrophages mainly through suppressing JNK/SIRT1/p65 signaling. These findings amplified the mechanisms of baicalin and its potential to attenuate insulin resistance.

Emerging role of NEDD8-mediated neddylation in age-related metabolic diseases.

Aging in humans is associated with abdominal distribution and remodeling of body fat and a parallel gradual increase in the prevalence of metabolic diseases such as obesity, type 2 diabetes mellitus and fatty liver disease, as well as the risk of developing metabolic complications. Current treatments might be improved by understanding the detailed mechanisms underlying the onset of age-related metabolic disorders. Neddylation, a post-translational modification that adds the ubiquitin-like protein NEDD8 to substrate proteins, has recently been linked to age-related metabolic diseases, opening new avenues of investigation and raising a potential target for treatment of these diseases. In this review, we will focus on the potential role of NEDD8-mediated neddylation in age-related metabolic dysregulation, insulin resistance, obesity, type 2 diabetes mellitus and fatty liver. We propose that alterations in NEDD8-mediated neddylation contribute to triggering insulin resistance and the development of age-related metabolic dysregulation, thus highlighting NEDD8 as a promising therapeutic target for preventing age-related metabolic diseases.

Cardioprotective effects of neuropeptide galanin: Focusing on its roles against diabetic heart.

Following an unprecedented rise in the number of the aged, the incidence of age-related diseases, such as diabetes and cardiovascular disease, is consequently increasing in the world. Type 2 diabetes mellitus (T2DM) is associated with excess cardiovascular morbidity and mortality. The diabetic heart is characterized by increased cardiomyocyte stiffness and fibrotic changes. Despite many factors resulting in cardiomyocyte injury and dysfunction in diabetes, insulin resistance is still a critical etiology of diabetic cardiomyopathy. Preclinical and clinical studies have revealed an intriguing role for galanin in the pathogenesis of insulin resistance and diabetic heart disease. A significant change in plasma galanin levels occurred in patients suffering from type 2 diabetes or cardiomyocyte injury. In turn, galanin may also distinctly mitigate hyperglycemia and insulin resistance in diabetes as well as increase glucose metabolism and mitochondrial biogenesis in cardiac muscle. Here, we critically review current data about the multivariate relationship among galanin, insulin resistance, and cardiac muscle to comprehensively evaluate the protective role of galanin and its receptors for the diabetic heart and to determine whether galanin receptor 2 agonists potentially represent a feasible way to treat diabetic cardiomyopathy in the future.

Adipose-Muscle crosstalk in age-related metabolic disorders: The emerging roles of adipo-myokines.

Obesity and type 2 diabetes account for a considerable proportion of the global burden of age-related metabolic diseases. In age-related metabolic diseases, tissue crosstalk and metabolic regulation have been primarily linked to endocrine processes. Skeletal muscle and adipose tissue are endocrine organs that release myokines and adipokines into the bloodstream, respectively. These cytokines regulate metabolic responses in a variety of tissues, including skeletal muscle and adipose tissue. However, the intricate mechanisms underlying adipose-muscle crosstalk in age-related metabolic diseases are not fully understood. Recent exciting evidence suggests that myokines act to control adipose tissue functions, including lipolysis, browning, and inflammation, whereas adipokines mediate the beneficial actions of adipose tissue in the muscle, such as glucose uptake and metabolism. In this review, we assess the mechanisms of adipose-muscle crosstalk in age-related disorders and propose that the adipokines adiponectin and spexin, as well as the myokines irisin and interleukin-6 (IL-6), are crucial for maintaining the body's metabolic balance in age-related metabolic disorders. In addition, these changes of adipose-muscle crosstalk in response to exercise or dietary flavonoid consumption are part of the mechanisms of both functions in the remission of age-related metabolic disorders. A better understanding of the intricate relationships between adipose tissue and skeletal muscle could lead to more potent therapeutic approaches to prolong life and prevent age-related metabolic diseases.

Emerging roles of histone deacetylases in adaptive thermogenesis.

Brown and beige adipose tissues regulate body energy expenditure through adaptive thermogenesis, which converts energy into heat by oxidative phosphorylation uncoupling. Although promoting adaptive thermogenesis has been demonstrated to be a prospective strategy for obesity control, there are few methods for increasing adipose tissue thermogenesis in a safe and effective way. Histone deacetylase (HDAC) is a category of epigenetic modifying enzymes that catalyzes deacetylation on both histone and non-histone proteins. Recent studies illustrated that HDACs play an important role in adipose tissue thermogenesis through modulating gene transcription and chromatin structure as well as cellular signals transduction in both deacetylation dependent or independent manners. Given that different classes and subtypes of HDACs show diversity in the mechanisms of adaptive thermogenesis regulation, we systematically summarized the effects of different HDACs on adaptive thermogenesis and their underlying mechanisms in this review. We also emphasized the differences among HDACs in thermogenesis regulation, which will help to find new efficient anti-obesity drugs targeting specific HDAC subtypes.

Acetylation of p65Lys310 by p300 in macrophages mediates anti-inflammatory property of berberine.

Nuclear factor (NF)-κB plays a pivotal role in the regulation of inflammatory response in macrophages. Berberine (BBR), which is an active constituent isolated from Coptis rhizome, possesses a prominent anti-inflammatory activity. Here we show that BBR changes the global acetylation landscape in LPS-induced protein acetylation of macrophages and reduces the acetylation of NF-κB subunit p65 at site Lys310(p65Lys310), leading to the inhibition of NF-κB translocation and transcriptional activity to suppress the expressions of inflammatory factors. BBR resists the inflammatory response in acute LPS-stimulated mice through downregulation of p65Lys310 acetylation in peritoneal macrophages. In obese mice, BBR alleviates the metabolic disorder and inflammation with the reduced acetylation of p65Lys310 in white adipose tissue. Furthermore, we demonstrate that BBR acts as a regulator of p65Lys310 by inhibiting the expression of p300 in macrophages. Our findings elucidate a new molecular mechanism for the anti-inflammatory effect of BBR via the p300/p65Lys310 axis.

Galanin peptide family as a modulating target for contribution to metabolic syndrome.

Metabolic syndrome (MetS) is defined as abdominal central obesity, atherogenic dyslipidemia, insulin resistance, glucose intolerance and hypertension. The rapid increasing prevalence of MetS and the consequent diseases, such as type 2 diabetes mellitus and cardiovascular disorder, are becoming a global epidemic health problem. Despite considerable research into the etiology of this complex disease, the precise mechanism underlying MetS and the association of this complex disease with the development of type 2 diabetes mellitus and increased cardiovascular disease remains elusive. Therefore, researchers continue to actively search for new MetS treatments. Recent animal studies have indicated that the galanin peptide family of peptides may increase food intake, glucose intolerance, fat preference and the risk for obesity and dyslipidemia while decreasing insulin resistance and blood pressure, which diminishes the probability of type 2 diabetes mellitus and hypertension. To date, however, few papers have summarized the role of the galanin peptide family in modulating MetS. Through a summary of available papers and our recent studies, this study reviews the updated evidences of the effect that the galanin peptide family has on the clustering of MetS components, including obesity, dyslipidemia, insulin resistance and hypertension. This line of research will further deepen our understanding of the relationship between the galanin peptide family and the mechanisms underlying MetS, which will help develop new therapeutic strategies for this complex disease.

Emerging central and peripheral actions of spexin in feeding behavior, leptin resistance and obesity.

Consumption of a high calorie diet with irregular eating and sedentary behavior habits is typical of the current suboptimal lifestyle, contributing to the development of metabolic diseases such as obesity and type 2 diabetes mellitus. Most notably, the disorder of adipokine secretion in visceral adiposity is a major contributor to metabolic diseases with advancing age. In this regard, spexin and leptin are established as anorexigenic adipokines that can modulate adipogenesis and glucose metabolism by suppressing food intake or increasing energy expenditure, respectively. Emerging evidence points out that spexin levels are lower in the serum and adipose tissue of patients with obesity and/or insulin resistance, whereas circulating levels of leptin are higher in obesity and comorbidities. In turn, spexin and leptin pharmacologically induce beneficial effects on the brain's modulation of food intake and energy expenditure. On the other hand, endocrine crosstalk via spexin and leptin has also been reported in patients suffering from obesity and diabetes. Spexin plays a crucial role in the regulation of leptin secretion and leptin resistance. It should therefore be taken into account that studying the role of spexin in leptin regulation will help us combat the pathologies of obesity caused by leptin resistance.

Baicalin protects against insulin resistance and metabolic dysfunction through activation of GALR2/GLUT4 signaling.

BACKGROUND: Type 2 diabetes mellitus is a complex metabolic disorder associated with obesity, glucose intolerance and insulin resistance. Activation of GALR2 has been proposed as a therapeutic target for the treatment of insulin resistance. The previous studies showed that baicalin could mitigate insulin resistance, but the detailed mechanism of baicalin on insulin resistance has not been fully explored yet. PURPOSE: In the present study, we evaluated whether baicalin mitigated insulin resistance via activation of GALR2 signaling pathway. STUDY DESIGN/METHODS: Baicalin (25 mg/kg/d and 50 mg/kg/d) and/or GALR2 antagonist M871 (10 mg/kg/d) were injected individually or in combinations into obese mice once a day for three weeks, and normal and GALR2 knockdown myotubes were treated with baicalin (100 µM and 400 µM) or metformin (4 mM) in the absence or presence of M871 (800 nM) for 12 h, respectively. The molecular mechanism was explored in skeletal muscle and L6 myotubes. RESULTS: The present findings showed that baicalin mitigated hyperglycemia and insulin resistance and elevated the levels of PGC-1α, GLUT4, p-p38MAPK, p-AKT and p-AS160 in skeletal muscle of obese mice. Strikingly, the baicalin-induced beneficial effects were abolished by GALR2 antagonist M871 in obese mice. In vitro, baicalin dramatically augmented glucose consumption and the activity of PGC1α-GLUT4 axis in myotubes through activation of p38MAPK and AKT pathways. Moreover, baicalin-induced elevations in glucose consumption related genes were abolished by GALR2 antagonist M871 or silencing of GALR2 in myotubes. CONCLUSIONS: The present study for the first time demonstrated that baicalin protected against insulin resistance and metabolic dysfunction mainly through activation of GALR2-GLUT4 signal pathway. Our findings identified that activation of GALR2-GLUT4 signal pathway by baicalin could be a new therapeutic approach to treat insulin resistance and T2DM in clinic.

Emerging Protective Actions of PGC-1α in Diabetic Nephropathy.

Renal impairment is affected by various mechanisms of oxidative stress, mitochondrial dysfunction, and basement membrane thickening, which are the major causes of renal dysfunction in diabetes. Of note, hyperglycemia-induced mitochondrial dysfunction has been identified as a common cause of diabetic nephropathy and renal impairment, and the decrease in PGC-1α expression brought on by hyperglycemia plays an immensurable role in both the reduction of mitochondrial biogenesis and the rise in oxidative stress. Reduced PGC-1α expression levels may occur with rising SGLT2-dependent increase of cytoplasmic sodium and protons in the renal cells of diabetes, even if the precise mechanism of hyperglycemia-induced disruption of PGC-1α expression has not been identified. Additionally, it has been observed that SGLT2 inhibitors enhance PGC-1α expression and activity and decrease cytoplasmic sodium and protons in many kidney cells, which may be helpful in reducing renal impairment brought on by diabetes. This review summarizes our and other recent studies on the function of PGC-1α in diabetic nephropathy, provides another potential mediator of the lower PGC-1α expression levels brought on by hyperglycemia in diabetics, and identifies a new pathogenesis of diabetes-related renal impairment. It also explains the mechanism underlying the protective effects of SGLT2 inhibitors on diabetic nephropathy. Therefore, it should be taken into account that SGLT2 inhibitors are an effective therapeutic strategy for reducing renal dysfunction caused by diabetes.

Exercise training rescues adipose tissue spexin expression and secretion in diet-induced obese mice.

Exercise training improves obesity-induced metabolic diseases through regulation of adipokines. Previous studies have shown that adipocyte-spexin participates in metabolic diseases such as obesity and diabetes via the modulation of energy homeostasis and insulin resistance. The objective of this research was to investigate the effects of swimming exercise on the levels of adipocyte-spexin and the underlying mechanisms. The normal chow diet (NC)-fed and high-fat diet (HFD)-fed mice were divided into exercise or sedentary groups. The expression and secretion of spexin in adipose tissue were assessed by quantitative real-time PCR and ELISA. The present findings uncovered the effect of exercise-induced spexin expression in the adipose tissue of obese mice. Besides, chronic exercise-induced upregulation of adipose spexin may be mediated by COUP-TF2 and KLF9. In addition, constant-moderate intensity exercise increased the levels of GLUT4, SIRT1 and PGC-1α in the skeletal muscles of mice. These results suggest that spexin is a potential mediator for exercise to ameliorate obesity-induced insulin resistance, namely, the beneficial effect of exercise on insulin sensitivity is at least partly mediated by spexin. Thus, exercise restores spexin production and release, which increases insulin sensitivity and maintains metabolic balance in the adipose tissues of HFD-induced obese mice.

Puffball spores improve wound healing in a diabetic rat model.

Persistent chronic oxidative stress is a primary pathogenic characteristics of diabetic foot ulcers. Puffball spores are a traditional Chinese medicine used to treat diabetic foot ulcers infections and bedsores. However, their effects against diabetic wounds and the mechanism underlying these effects remain largely unknown. The present study explored the effectiveness of puffball spores in diabetic wound treatment and the mechanisms underlying their effects. Sprague-Dawley rats with streptozotocin (STZ)-induced diabetes were treated with puffball spores to ascertain whether they accelerated wound healing.Real-time quantitative PCR, western blotting, hematoxylin-eosin and Masson's trichrome staining, immunohistochemistry analysis, and immunofluorescence assays were performed. As indicated by wound and serum histology and biochemical analyses, the puffball spores accelerated wound healing by activating Akt/Nrf2 signaling and promoting the expression of its downstream antioxidant genes, markedly stimulating antioxidant activity and enhanceing angiogenesis and collagen deposition. Our findings showed that puffball spores could accelerate diabetic wound healing, enhance antioxidant ability, promote the expression of vascular markers, and suppress inflammation, thus providing a theoretical basis for the treatment of diabetic and refractory wounds.

Adipose tissue spexin in physical exercise and age-associated diseases.

It is known that a strong association exists between a suboptimal lifestyle (physical inactivity and sedentary behavior and/or high calorie diet) and increased propensity of developing age-associated diseases, such as obesity and T2DM. Physical exercise can alleviate obesity-induced insulin resistance and T2DM, however, the precise mechanism for this outcome is not fully understood. The endocrine disorder of adipose tissue in obesity plays a critical role in the development of insulin resistance. In this regard, spexin has been recently described as an adipokine that plays an important role in the pathophysiology of obesity-induced insulin resistance and T2DM. In obese states, expression of adipose tissue spexin is reduced, inducing the adipose tissue and skeletal muscle more susceptible to insulin resistance. Emerging evidences point out that exercise can increase spexin expression. In return, spexin could exert the exercise-protective roles to ameliorate insulin resistance, suggesting that spexin is a potential mediator for exercise to ameliorate obesity-induced insulin resistance and T2DM, namely, the beneficial effect of exercise on insulin sensitivity is at least partly mediated by spexin. This review summarizes our and others' recent studies regarding the effects of obesity on adipose tissue spexin induction, along with the potential effect of exercise on this response in obese context, and provides a new insight into the multivariate relationship among exercise, spexin and T2DM. It should be therefore taken into account that a combination of spexin and exercise training is an effective therapeutic strategy for age-associated diseases.

Treatment with spexin mitigates diet-induced hepatic steatosis in vivo and in vitro through activation of galanin receptor 2.

It was reported that spexin as an adipocyte-secreted protein could regulate obesity and insulin resistance. However, the specific metabolic contribution of spexin to fatty liver remains incompletely understood. Herein, we investigated the effects of spexin on hepatosteatosis and explored the underlying molecular mechanisms. HFD-fed mice were injected with spexin and/or GALR2 antagonist M871, while PA-induced HepG2 cells were treated with spexin in the absence or presence of M871 for 12 h, respectively. Gene expression in liver tissues and hepatocytes was assessed by qRT-PCR and western blotting, respectively. The results showed that body weight, visceral fat content, liver lipid droplet formation, hepatic intracellular triglyceride, and serum triglyceride were reduced in spexin-treated mice. Furthermore, spexin increased the expression of hepatic CPT1A, PPARα, SIRT1, KLF9, PGC-1α and PEPCK in vivo and in vitro. Additionally, spexin treatment improved glucose tolerance and insulin sensitivity in mice fed the HFD. Interestingly, these spexin-mediated beneficial effects were abolished by the GALR2 antagonist M871 in mice fed HFD and PA-induced HepG2 cells, suggesting that spexin mitigated HFD-induced hepatic steatosis by activating the GALR2, thereby increasing CPT1A, PPARα, SIRT1, KLF9, PGC-1α and PEPCK expression. Taken together, these data suggest that spexin ameliorates NAFLD by improving lipolysis and fatty acid oxidation via activation of GALR2 signaling.