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.

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.

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.

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 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.

Upregulation of adiponectin by Ginsenoside Rb1 contributes to amelioration of hepatic steatosis induced by high fat diet.

Background: Ginsenoside Rb1 (GRb1) is capable of regulating lipid and glucose metabolism through its action on adipocytes. However, the beneficial role of GRb1-induced up-regulation of adiponectin in liver steatosis remains unelucidated. Thus, we tested whether GRb1 ameliorates liver steatosis and insulin resistance by promoting the expression of adiponectin. Methods: 3T3-L1 adipocytes and hepatocytes were used to investigate GRb1's action on adiponectin expression and triglyceride (TG) accumulation. Wild type (WT) mice and adiponectin knockout (KO) mice fed high fat diet were treated with GRb1 for 2 weeks. Hepatic fat accumulation and function as well as insulin sensitivity was measured. The activation of AMPK was also detected in the liver and hepatocytes. Results: GRb1 reversed the reduction of adiponectin secretion in adipocytes. The conditioned medium (CM) from adipocytes treated with GRb1 reduced TG accumulation in hepatocytes, which was partly attenuated by the adiponectin antibody. In the KO mice, the GRb1-induced significant decrease of TG content, ALT and AST was blocked by the deletion of adiponectin. The elevations of GRb1-induced insulin sensitivity indicated by OGTT, ITT and HOMA-IR were also weakened in the KO mice. The CM treatment significantly enhanced the phosphorylation of AMPK in hepatocytes, but not GRb1 treatment. Likewise, the phosphorylation of AMPK in liver of the WT mice was increased by GRb1, but not in the KO mice. Conclusions: The up-regulation of adiponectin by GRb1 contributes to the amelioration of liver steatosis and insulin resistance, which further elucidates a new mechanism underlying the beneficial effects of GRb1 on obesity.

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.

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.

Spexin ameliorates skeletal muscle insulin resistance through activation of GAL2 receptor.

Skeletal muscle is a principal tissue involved in energy expenditure and glucose metabolism. Although the results of our and other studies show that spexin could decrease food intake and obesity, the specific metabolic effect of spexin on glucose metabolism of skeletal muscle is still unclear. The aim of this study is to investigate whether spexin might mitigate obesity-induced insulin resistance in skeletal muscles and to explore its underlying mechanisms. The high fat diet-fed mice were treated with 50 µg/kg/d spexin for 21 consecutive days, and the differentiated myotubes of L6 were treated with spexin (200, 400, 800 nM) in the absence or presence of M871 (800 nM) for 12 h respectively. Besides, the galanin type 2 (GAL2) receptor knockdown myotubes were treated with 800 nM spexin for 12 h in this study. The present findings showed that spexin reversed hyperglycemia and glucose intolerance as well as insulin intolerance and insulin resistance in the mice fed with high fat diet. Furthermore, spexin markedly augmented the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) expression and deacetylation, and further triggered glucose transporter 4 (GLUT4) expression and trafficking in myotubes through p38 mitogen-activated protein kinase (P38MAPK) and protein kinase B (AKT) activation. More importantly, the elevation of glucose consumption related genes by spexin were abolished by GAL2 receptor antagonist or silencing of GAL2 receptor in myotubes. In conclusion, our findings provide a novel insight that spexin can protect against insulin resistance and increase glucose consumption in skeletal muscles mainly through activation of GAL2/GLUT4 signal pathway. Spexin might therefore be a novel therapeutic target for hyperglycemia and insulin resistance in clinic.

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.

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.

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 roles of kisspeptin/galanin in age-related metabolic disease.

Age is a major risk factor for developing metabolic diseases such as obesity and diabetes. There is an unprecedented rise in obesity and type 2 diabetes in recent decades. A convincing majority of brain-gut peptides are associated with a higher risk to develop metabolic disorders, and may contribute to the pathophysiology of age-related metabolic diseases. Accumulating basic studies revealed an intriguing role of kisspeptin and galanin involved in the amelioration of insulin resistance in different ways. In patients suffered from obesity and diabetes a significant, sex-related changes in the plasma kisspeptin and galanin levels occurred. Kisspeptin is anorexigenic to prevent obesity, its level is negatively correlative with obesity and insulin resistance. While galanin is appetitive to stimulate food intake and body weight, its level is positively correlative with obesity, HOMA-IR and glucose/triglyceride concentration. In turn, kisspeptin and galanin also distinctly increase glucose uptake and utilization as well as energy expenditure. This article reviews recent evidence dealing with the role of kisspeptin and galanin in the pathophysiology of age-related metabolic diseases. It should be therefore taken into account that the targeted modulation of those peptidergic signaling may be potentially helpful in the future treatment of age-related metabolic diseases.

Loss of chemerin triggers bone remodeling in vivo and in vitro.

OBJECTIVE: It was reported that chemerin as an adipocyte-secreted protein could regulate bone resorption and bone formation. However, the specific molecular and gene mechanism of the chemerin role is unclear. The aim of this study is to evaluate the role of chemerin in bone metabolism. METHODS: In the present study, we investigated the effects of chemerin on bone remodeling in rarres2 knockout (Rarres2-/-) mice and examined the role of chemerin as a determinant of osteoblast and osteoclast differentiation in Mc3t3-E1 and Raw264.7 cell lines. RESULTS: The results showed that the bone mineral density and volume score, trabecular thickness, weight and bone formation marker BALP increased, but Tb.Sp and bone resorption marker TRACP-5b decreased in Rarres2-/- mice. Furthermore, the mRNA and protein expression of biomarkers of osteoblasts (ß-catenin, RANKL and OPG) significantly increased, but those of osteoclasts (CTSK and RANK) decreased in Rarres2-/- mice. In vitro, chemerin markedly suppressed ß-catenin and OPG, but increased RANKL, CTSK and RANK expression. Moreover, knockdown of chemerin using RNA interference enhanced osteoblastogenesis genes and inhibited osteoclastogenesis genes in Mc3t3-E1 and Raw264.7 cells. CONCLUSIONS: Taken together, these data suggest an inhibitive effect of chemerin on osteoblast differentiation and proliferation through inhibition of Wnt/ß-catenin signaling, as well as a stimulative effect of chemerin on osteoclast differentiation and proliferation via activation of RANK signaling. The maintenance of a low chemerin level may be a strategy for the prevention and treatment of osteoporosis.

Development of metabolic dysfunction in mice lacking chemerin.

Chemerin, an adipocyte-secreted adipokine, is hypothesized to participate in energy homeostasis and glucoregulation. However, the physiologic effect of endogenous chemerin on glucose metabolism is unclear. The present studies tested the hypotheses that chemerin deficiency alters whole-body glucose homeostasis following switches to high-fat diet. Adult, male chemerin knockout and C57BL/6J control wild type mice were studied. During the following 4 weeks, chow- or high-fat diet maintained chemerin knockout mice showed elevated fasting glucose levels and glucose intolerance as well as insulin intolerance. Chemerin deficiency impaired adaptation to glucose and insulin challenge, leading to increased glucose levels. Moreover, the mRNA and protein levels of GLUT4 and PGC-1α expression in both skeletal muscle and adipose tissue were significantly decreased in chemerin knockout mice relative to the wild type, respectively. Taken together, the results support the hypotheses that chemerin helps adapt glucose metabolism to changes in dietary fat and modulates glucose consumption in mice by activation of PGC-1α/GLUT4 axis. Chemerin may play a significant role in elevation of glucose uptake and insulin sensitivity to promote glucose clearance.

Time-restricted feeding attenuates gluconeogenic activity through inhibition of PGC-1α expression and activity.

BACKGROUND: Time-restricted feeding (TRF), a key component of intermittent fasting regimens, has gained considerable attention in recent years due to reversing obesity and insulin resistance. To the best of our knowledge, here, we reported for the first time the underlying mechanistic therapeutic efficacy of TRF against hepatic gluconeogenic activity in obese mice. METHODS: The obese mice were subjected to either ad lib or TRF of a high fat diet for 8 h per day for 4 weeks. Western blotting, qRT-PCR, and plasma biochemical analyses were applied. RESULTS: The present findings showed that TRF regimen reduced food intake, and reversed high fat diet-induced glucose intolerance, hyperglycemia and insulin resistance in mice of high fat diet-induced obesity. Mechanistically, we confirmed that TRF regimen protected against hyperglycemia and ameliorated hepatic gluconeogenic activity through inhibition of p38 MAPK/SIRT1/PGC-1α signal pathway. CONCLUSION: Our findings suggest that TRF regimen might be a potential novel nonpharmacological strategy against obesity/diabetes-induced hyperglycemia and insulin resistance.