AMPK In Adipose Tissue Research Articles

Effects of aerobic training and vitamin D supplementation on glycemic indices and adipose tissue gene expression in type 2 diabetic rats

Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder mainly caused by overweight and obesity that accumulates pro-inflammatory factors in adipose tissue. Studies have confirmed the efficacy of exercise and vitamin D supplementation in preventing, controlling, and treating diabetes. While, reduced physical activity and vitamin D deficiency are related to increased adiposity, blood glucose level, insulin concentration, and insulin resistance. This study purposed to investigate the effect of 8-week aerobic training with vitamin D supplementation on the expression of AMPK, PGC-1α, and UCP-1 genes expression in the visceral adipose tissue of obese rats with T2DM. In this experimental study, fifty male Wistar rats were divided into 5 groups (n = 10): aerobic training and vitamin D supplementation (AT + Vit D), aerobic training (5 days/week for 8 weeks; AT), vitamin D supplementation (Vit D), diabetic control (C) and NC (Non-Diabetic Control). AT + Vit D and AT groups practiced an 8-week aerobic training, 5 days a week. Vit D and AT + Vit D groups receive 5000 IU of vitamin D by injection once a week while AT and C received sesame oil. After blood sampling, visceral fat was taken to measure AMPK, PGC-1α, and UCP1 gene expression. Data were statistically analyzed by One-way ANOVA and paired sample t-test at a significance level of p < 0.05. Based on our results BW, BMI, WC, visceral fat, insulin, glucose, and HOMA-IR were significantly lower in the AT + Vit D, AT, and Vit D groups compared with the C group (p < 0.01). Furthermore, AT + Vit D, AT, and Vit D upregulated AMPK, PGC-1α, and UCP1 gene expression compared to the C. Based on the results compared to AT and Vit D, AT + Vit D significantly upregulated AMPK (p = 0.004; p = 0.001), PGC-1α (p = 0.010; p = 0.001), and UCP1 (p = 0.032; p = 0.001) gene expression, respectively. Also, AT induced more significant upregulations in the AMPK (p = 0.001), PGC-1α (p = 0.001), and UCP1 gene expression (p = 0.001) than Vit D. Vitamin D supplementation enhanced the beneficial effects of aerobic training on BW, BMI, WC, visceral fat, insulin, glucose, and HOMA-IR in diabetic rats. We also observed that separate AT or Vit D upregulated the gene expression of AMPK, PGC-1α, and UCP1 however, combined AT + Vit D upregulated AMPK, PGC-1α, and UCP1 more significantly. These results suggested that combining aerobic training and vitamin D supplementation exerted incremental effects on the gene expressions related to adipose tissue in animal models of diabetes.

Sargassum thunbergii Extract Attenuates High-Fat Diet-Induced Obesity in Mice by Modulating AMPK Activation and the Gut Microbiota.

Sargassum thunbergii (Mertens ex Roth) Kuntze (ST) is a brown alga rich in indole-2-carboxaldehyde. This study aimed to investigate the anti-obesity effects of ethanol extract from ST in in vitro and in vivo models. In 3T3-L1 cells, ST extract significantly inhibited lipid accumulation in mature adipocytes while lowering adipogenic genes (C/epba and Pparg) and enhancing metabolic sensors (Ampk, Sirt1), thermogenic genes (Pgc-1a, Ucp1), and proteins (p-AMPK/AMPK and UCP1). During animal investigation, mice were administered a chow diet, a high-fat diet (HF), or an HF diet supplemented with ST extract (at dosages of 150 and 300 mg/kg bw per day) for 8 weeks (n = 10/group). ST extract administration decreased weight gain, white adipose tissue weight, LDL-cholesterol, and serum leptin levels while improving glucose intolerance. In addition, ST extract increased the expression of Ampk and Sirt1 in adipose tissue and in the liver, as well as p-AMPK/AMPK ratio in the liver, compared to HF-fed mice. The abundance of Bacteroides vulgatus and Faecalibacterium prausnitzii in the feces increased in response to ST extract administration, although levels of Romboutsia ilealis decreased compared with those in HF-fed mice. ST extract could prevent obesity in HF-fed mice via the modulation of AMPK activation and gut microbiota composition.

Sexually dimorphic metabolic effects of a naturally occurring flavonoid are mediated by changes in the gut microbiome

It is increasingly understood that dietary flavonoids modulate the gut microbiome which influences host metabolism. However, sex‐dependent effects of flavonoids on the gut microbiome composition and metabolic health have not been studied. In this regard, we have previously shown that an oral flavonoid 7,8‐Dihydroxyflavone (DHF), exerts sexually‐dimorphic effects on body weight and metabolic health. Specifically, oral DHF supplementation prevents HFD‐induced obesity and inflammation in female but not male mice. Interestingly, this metabolic protection was associated with early and stable changes in the composition of the female, but not male, gut microbiome. The remodeled female microbiome contributed to increased formation of the short chain fatty acid acetate, while male mice did not display a similar effect. While a causal association between the gut microbiome and metabolic protection in female mice was not previously studied, we now demonstrate using a model of antibiotic‐induced gut microbiome ablation, that an intact microbiome is required to mediate metabolic protection due to DHF in female mice. Upon ablation of the gut microbiome DHF supplementation not only did not prevent HFD‐induced obesity in female mice, it also failed to activate the TrkB receptor, whose activity has been previously ascribed to metabolic signaling by DHF. Mechanistically, we report that metabolic protection in female mice is mediated by increased thermogenic markers including UCP1, AMPK, SIRT1, and PGF‐1α in brown adipose tissue in females, but not males. This thermogenic activation also required an intact gut microbiome. These results reveal complex and novel interactions between dietary flavonoids, sex, and the gut microbiome that have important implications both to understanding the etiology of metabolic diseases and for the development of personalized nutrition strategies for their prevention.

Anti-obesity effect of Cydonia oblonga Miller extract in high-fat diet-induced obese C57BL/6 mice

• Cydonia oblonga Miller extract (COME) exerts anti-obesity effect in obese mouse. • COME reduces white adipose tissue deposition in high-fat diet induced obese mice. • COME induces the activation of AMPK in epididymal adipose tissue. • COME modulates adipogenic transcription factors and their target genes expressions. The present study was designed to explore whether Cydonia oblonga Miller extract (COME) had anti-obesity effects and the mechanism involved. COME reduced body weight, fat mass, adipose tissue weight, and serum levels of insulin, triglyceride, and leptin, but increased the serum levels of adiponectin and high-density lipoprotein-cholesterol in high-fat diet (HFD)-induced obese C57BL/6 mice. COME increased AMPK activation. COME suppressed adipogenesis by decreasing CCAAT/enhancer binding protein α, peroxisome proliferator-activated receptor γ, sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase 1, ATP-citrate lyase, fatty acid synthase, and adipocyte protein 2 mRNA expression and enhanced lipolysis by increasing carnitine palmitoyl transferase 1 and hormone sensitive lipase mRNA expression. These results suggest that COME is potentially beneficial in inhibiting HFD-induced obesity by inducing AMPK activation and thereby, regulating several pathways involved in inhibiting adipogenesis, and promoting lipolysis and fatty acid oxidation. Our results suggest that COM may be used as an anti-obesity agent.

Elaiophylin reduces body weight and lowers glucose levels in obese mice by activating AMPK

Obesity is an epidemic affecting 13% of the global population and increasing the risk of many chronic diseases. However, only several drugs are licensed for pharmacological intervention for the treatment of obesity. As a master regulator of metabolism, the therapeutic potential of AMPK is widely recognized and aggressively pursued for the treatment of metabolic diseases. We found that elaiophylin (Ela) rapidly activates AMPK in a panel of cancer-cell lines, as well as primary hepatocytes and adipocytes. Meanwhile, Ela inhibits the mTORC1 complex, turning on catabolism and turning off anabolism together with AMPK. In vitro and in vivo studies showed that Ela does not activate AMPK directly, instead, it increases cellular AMP/ATP and ADP/ATP ratios, leading to AMPK phosphorylation in a LKB1-dependent manner. AMPK activation induced by Ela caused changes in diverse metabolic genes, thereby promoting glucose consumption and fatty acid oxidation. Importantly, Ela activates AMPK in mouse liver and adipose tissue. As a consequence, it reduces body weight and blood glucose levels and improves glucose and insulin tolerance in both ob/ob and high-fat diet-induced obese mouse models. Our study has identified a novel AMPK activator as a candidate drug for the treatment of obesity and its associated chronic diseases.

Lipocalin-type Prostaglandin D2 Synthase appears to function as a Novel Adipokine Preventing Adipose Dysfunction in response to a High Fat Diet

Adipose dysfunction is the primary defect in obesity that contributes to the development of dyslipidemia, insulin resistance, cardiovascular diseases, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and some cancers. Previously, we demonstrated the development of NAFLD in lipocalin-type prostaglandin D2 synthase (L-PGDS) knockout mice regardless of diet. In the present study, we examined the role of L-PGDS in adipose in response to a high fat diet. We observed decreased expression of L-PGDS in adipose tissue and concomitant lower plasma levels in a dietary model of obesity as well as in insulin resistant 3T3-L1 adipocytes. We show reduced adiponectin expression and phosphorylation of AMPK in white adipose tissue of L-PGDS KO mice after 14 weeks on a high fat diet as compared to control C57BL/6 mice. We also observe an increased fat content in L-PGDS KO mice as demonstrated by adipocyte hypertrophy and increased expression of lipogenenic genes. We confirmed our in vivo findings in in vitro 3T3-L1 adipocytes, using an enzymatic inhibitor of L-PGDS (AT56). Rosiglitazone treatment drastically increased L-PGDS expression in insulin resistant 3T3-L1 adipocytes and increased adiponectin expression and AMPK phosphorylation in AT56 treated 3T3-L1 adipocytes. We conclude that the absence of L-PGDS has a deleterious effect on adipose tissue functioning, which further reduces insulin sensitivity in adipose tissue. Consequently, we propose L-PGDS appears to function as a potential member of the adipokine secretome involved in the regulation of the obesity-associated metabolic syndrome.

Regulation of metabolism during hibernation in brown bears (Ursus arctos): Involvement of cortisol, PGC-1α and AMPK in adipose tissue and skeletal muscle

The purpose of this study was to investigate changes in expression of known cellular regulators of metabolism during hyperphagia (Sept) and hibernation (Jan) in skeletal muscle and adipose tissue of brown bears and determine whether signaling molecules and transcription factors known to respond to changes in cellular energy state are involved in the regulation of these metabolic adaptations. During hibernation, serum levels of cortisol, glycerol, and triglycerides were elevated, and protein expression and activation of AMPK in skeletal muscle and adipose tissue were reduced. mRNA expression of the co-activator PGC-1α was reduced in all tissues in hibernation whereas mRNA expression of the transcription factor PPAR-α was reduced in the vastus lateralis muscle and adipose tissue only. During hibernation, gene expression of ATGL and CD36 was not altered; however, HSL gene expression was reduced in adipose tissue. During hibernation gene expression of the lipogenic enzyme DGAT in all tissues and the expression of the FA oxidative enzyme LCAD in the vastus lateralis muscle were reduced. Gene and protein expression of the glucose transporter GLUT4 was decreased in adipose tissue in hibernation. Our data suggest that high cortisol levels are a key adaptation during hibernation and link cortisol to a reduced activation of the AMPK/PGC-1α/PPAR-α axis in the regulation of metabolism in skeletal muscle and adipose tissue. Moreover, our results indicate that during this phase of hibernation at a time when metabolic rate is significantly reduced metabolic adaptations in peripheral tissues seek to limit the detrimental effects of unduly large energy dissipation.

EGCG Reduces Obesity and White Adipose Tissue Gain Partly Through AMPK Activation in Mice

(-)-Epigallocatechin-3-gallate (EGCG), which is the most abundant catechin in green tea, has many potential health benefits, including decreased weight gain and/or adipose tissue weight. Suggested mechanisms for body weight reduction by EGCG include: (1) a decrease in calorie intake and (2) activation of AMPK in liver, skeletal muscle, and white adipose tissue. However, only one study supports the AMPK hypothesis. To determine the role of AMPK in EGCG-induced reduction of body weight, we administrated 50 mg/kg and 100 mg/kg per day to mice, together with a high-fat diet (HFD), for 20 weeks. EGCG had a significant effect on obesity and decrease in epididymal adipose tissue weight, and also affected serum lipid characteristics, including triglyceride, cholesterol (CHOL), and high- and low-density lipoprotein CHOL (HDL-C, LDL-C) concentrations. In addition, EGCG increased the excretion of free fatty acids from feces. By measuring the mRNA expression levels of genes involved in lipid metabolism, we found that EGCG inhibited the expression of genes involved in the synthesis of de novo fatty acids (acc1, fas, scd1, c/ebpβ, pparγ, and srebp1) and increased the expression of genes associated with lipolysis (hsl) and lipid oxidization in white adipose tissue, in both the HFD and the EGCG groups. However, EGCG significantly increased the expression of genes involved in the synthesis of de novo fatty acids compared with the HFD group. Increased AMPK activity was found in both subcutaneous and epididymal adipose tissues. In conclusion, EGCG can decrease obesity and epididymal white adipose tissue weight in mice, only partially via activation of AMPK.

TRB3 gene silencing activates AMPK in adipose tissue with beneficial metabolic effects in obese and diabetic rats

Our previous study had suggested Tribbles homolog 3 (TRB3) might be involved in metabolic syndrome via adipose tissue. Given prior studies, we sought to determine whether TRB3 plays a major role in adipocytes and adipose tissue with beneficial metabolic effects in obese and diabetic rats. Fully differentiated 3T3-L1 adipocytes were incubated to induce insulin resistant adipocytes. Forty male Sprague–Dawley rats were all fed high-fat (HF) diet. Type 2 diabetic rat model was induced by high-fat diet and low-dose streptozotocin (STZ). Compared with control group, in insulin resistant adipocytes, protein levels of insulin receptor substrate-1(IRS-1), glucose transporter 4(GLUT4) and phosphorylated-AMP-activated protein kinase (p-AMPK)were reduced, TRB3 protein level and triglyceride level were significantly increased, glucose uptake was markedly decreased. TRB3 silencing alleviated adipocytes insulin resistance. With TRB3 gene silencing, protein levels of IRS-1, GLUT4 and p-AMPK were significantly increased in adipocytes. TRB3 gene silencing decreased blood glucose, ameliorated insulin sensitivity and adipose tissue remodeling in diabetic rats. TRB3 silencing decreased triglyceride, increased glycogen simultaneously in diabetic epididymal and brown adipose tissues (BAT). Consistently, p-AMPK levels were increased in diabetic epididymal adipose tissue, and BAT after TRB3-siRNA treatment. TRB3silencing increased phosphorylation of Akt in liver, and improved liver insulin resistance.

Metformin and resveratrol inhibit Drp1-mediated mitochondrial fission and prevent ER stress-associated NLRP3 inflammasome activation in the adipose tissue of diabetic mice

ObjectiveThis study was designed to investigate the hypothesis that metformin and resveratrol exhibited the same effect on inhibition of NLRP3 inflammasome activation with regulation of AMPK in adipose tissue exposed to high glucose. MethodsTo induce adipose tissue dysfunction, we treated epididymal adipose tissue of mice or differentiated 3T3-L1 adipocytes with high glucose (33 mM) for 24 h. Meanwhile, mice were injected with streptozotocin STZ to induce diabetes and followed by oral administration of metformin (200 mg/kg), resveratrol (50 mg/kg) or ER stress inhibitor TUDCA (50 mg/kg) for 7 days. The effects of metformin and resveratrol on ROS production, mitochondrial fission, ER stress, TXNIP/NLRP3 inflammasome activation, inflammation and apoptosis were observed. ResultsMetformin and resveratrol inhibited ROS-associated mitochondrial fission by upregulating Drp1 phosphorylation (Ser 637) in an AMPK-dependent manner, and then suppressed ER stress indicated by dephosphorylation of IRE1α and eIF2α in the adipose tissue. As a result from suppressing TXNIP/NLRP3 inflammasome activation, metformin and resveratrol inhibited inflammation and reduced cell apoptosis in adipose tissue or adipocytes exposed to high glucose. ConclusionMetformin and resveratrol protected mitochondrial integrity by inhibiting Drp1 activity and prevented NLRP3 inflammasome activation by suppressing ER stress, and thereby protected adipose function from high glucose insult.

Improved Insulin Sensitivity 3 Months After RYGB Surgery Is Associated With Increased Subcutaneous Adipose Tissue AMPK Activity and Decreased Oxidative Stress.

Morbidly obese individuals are predisposed to a wide range of disorders, including type 2 diabetes, atherosclerotic cardiovascular disease, fatty liver disease, and certain cancers. Remarkably, all of these disorders can be improved or prevented by Roux-en-Y gastric bypass (RYGB) surgery. We have reported that decreased AMPK activity, together with increased oxidative stress and inflammation in adipose tissue, is associated with insulin resistance in morbidly obese bariatric surgery patients. In the current study, we assessed how these parameters are affected by RYGB surgery. Eleven patients (average age of 46 ± 4 years) were studied immediately prior to surgery and 3 months postoperatively. We measured subcutaneous adipose tissue AMPK phosphorylation (threonine 172, an index of its activation), malonyl-CoA content, protein carbonylation (a marker of oxidative stress), plasma adiponectin, and mRNA expression of several inflammatory cytokines. After surgery, AMPK activity increased 3.5-fold and oxidative stress decreased by 50% in subcutaneous adipose tissue. In addition, malonyl-CoA levels were reduced by 80%. Furthermore, patients had improvements in their BMI and insulin sensitivity (HOMA) and had increased circulating high–molecular weight adiponectin and decreased fasting plasma insulin levels. In contrast, the expression of inflammatory markers in subcutaneous adipose tissue was unchanged postoperatively, although plasma CRP was diminished by 50%.

Effects of Biotin Supplementation in the Diet on Adipose Tissue cGMP Concentrations, AMPK Activation, Lipolysis, and Serum-Free Fatty Acid Levels.

Several studies have shown that pharmacological concentrations of biotin decrease hyperlipidemia. The molecular mechanisms by which pharmacological concentrations of biotin modify lipid metabolism are largely unknown. Adipose tissue plays a central role in lipid homeostasis. In the present study, we analyzed the effects of biotin supplementation in adipose tissue on signaling pathways and critical proteins that regulate lipid metabolism, as well as on lipolysis. In addition, we assessed serum fatty acid concentrations. Male BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet (control: 1.76 mg biotin/kg; supplemented: 97.7 mg biotin/kg diet) over 8 weeks postweaning. Compared with the control group, biotin-supplemented mice showed an increase in the levels of adipose guanosine 3',5'-cyclic monophosphate (cGMP) (control: 30.3±3.27 pmol/g wet tissue; supplemented: 49.5±3.44 pmol/g wet tissue) and of phosphorylated forms of adenosine 5'-monophosphate-activated protein kinase (AMPK; 65.2%±1.06%), acetyl-coenzyme A (CoA), carboxylase-1 (196%±68%), and acetyl-CoA carboxylase-2 (78.1%±18%). Serum fatty acid concentrations were decreased (control: 1.12±0.04 mM; supplemented: 0.91±0.03 mM), and no change in lipolysis was found (control: 0.29±0.05 μmol/mL; supplemented: 0.33±0.08 μmol/mL). In conclusion, 8 weeks of dietary biotin supplementation increased adipose tissue cGMP content and protein expression of the active form of AMPK and of the inactive forms of acetyl-CoA carboxylase-1 and acetyl-CoA carboxylase-2. Serum fatty acid levels fell, and no change in lipolysis was observed. These findings provide insight into the effects of biotin supplementation on adipose tissue and support its use in the treatment of dyslipidemia.

Effect of a new dietary SIRT1 activator on high fat diet‐induced obesity and the involvement of microRNAs

SIRT1 plays a key role in regulating metabolism, and SIRT1 activation may be a promising strategy to treat metabolic syndrome. This study investigated whether zerumbone ameliorated diet‐induced obesity through SIRT1 activation. We used differentiated 3T3‐L1 fibroblasts to examine the effect of zerumbone on adipogenesis through the miR‐146b‐SIRT1 cascade. To investigate the anti‐obesity effect of zerumbone in vivo, we fed zerumbone to high‐fat diet‐induced obese C57BL/6J mice for 8 weeks and measured body weight, adipose tissue size, and blood lipid profiles. We also measured the effect of zerumbone supplementation on SIRT1 and AMPK signaling pathways in the white adipose tissue of these mice. Zerumbone inhibited adipogenesis through the miR146b‐SIRT1 pathway and significantly reduced diet‐induced obesity in mice. Zerumbone supplementation was associated with miR‐146b downregulation, followed by SIRT1 activation and the deacetylation of FOXO1 and PGC1α, respectively, in the white adipose tissue of these mice. Zerumbone also activated AMPK and modulated lipid metabolism in adipose tissue by increasing fatty acid oxidation and reducing adipogenesis gene expression, respectively. Zerumbone inhibited adipogenesis via the miR‐146b/SIRT1 pathway and ameliorated diet‐induced obesity in mice via SIRT1 activation, suggesting that zerumbone could target obesity‐related metabolic disorders through its stimulation of SIRT1 activity.

An examination of resveratrol's mechanisms of action in human tissue: impact of a single dose in vivo and dose responses in skeletal muscle ex vivo.

The current study tested the hypothesis that a single, moderate dose of RSV would activate the AMPK/SIRT1 axis in human skeletal muscle and adipose tissue. Additionally, the effects of RSV on mitochondrial respiration in PmFBs were examined. Eight sedentary men (23.8±2.4 yrs; BMI: 32.7±7.1) reported to the lab on two occasions where they were provided a meal supplemented with 300 mg of RSV or a placebo. Blood samples, and a muscle biopsy were obtained in the fasted state and again, with the addition of an adipose tissue biopsy, two hours post-prandial. The effect of RSV on mitochondrial respiration was examined in PmFBs taken from muscle biopsies from an additional eight men (23.4±5.4 yrs; BMI: 24.4±2.8). No effect of RSV was observed on nuclear SIRT1 activity, acetylation of p53, or phosphorylation of AMPK, ACC or PKA in either skeletal muscle or adipose tissue. A decrease in post absorptive insulin levels was accompanied by elevated skeletal muscle phosphorylation of p38 MAPK, but no change in either skeletal muscle or adipose tissue insulin signalling. Mitochondrial respiration in PmFBs was rapidly inhibited by RSV at 100–300 uM depending on the substrate examined. These results question the efficacy of a single dose of RSV at altering skeletal muscle and adipose tissue AMPK/SIRT1 activity in humans and suggest that RSV mechanisms of action in humans may be associated with altered cellular energetics resulting from impaired mitochondrial ATP production.

The CB1 receptor mediates the peripheral effects of ghrelin on AMPK activity but not on growth hormone release

This study aimed to investigate whether the growth hormone release and metabolic effects of ghrelin on AMPK activity of peripheral tissues are mediated by cannabinoid receptor type 1 (CB1) and the central nervous system. CB1-knockout (KO) and/or wild-type mice were injected peripherally or intracerebroventricularly with ghrelin and CB1 antagonist rimonabant to study tissue AMPK activity and gene expression (transcription factors SREBP1c, transmembrane protein FAS, enzyme PEPCK, and protein HSL). Growth hormone levels were studied both in vivo and in vitro. Peripherally administered ghrelin in liver, heart, and adipose tissue AMPK activity cannot be observed in CB1-KO or CB1 antagonist-treated mice. Intracerebroventricular ghrelin treatment can influence peripheral AMPK activity. This effect is abolished in CB1-KO mice and by intracerebroventricular rimonabant treatment, suggesting that central CB1 receptors also participate in the signaling pathway that mediates the effects of ghrelin on peripheral tissues. Interestingly, in vivo or in vitro growth hormone release is intact in response to ghrelin in CB1-KO animals. Our data suggest that the metabolic effects of ghrelin on AMPK in peripheral tissues are abolished by the lack of functional CB1 receptor via direct peripheral effect and partially through the central nervous system, thus supporting the existence of a possible ghrelin-cannabinoid-CB1-AMPK pathway.

Air-pollution mediated susceptibility to inflammation and insulin resistance via CCR2 dependent and independent effects (P6246)

Abstract Epidemiologic and experimental studies support an association between fine ambient particulate matter &amp;lt;2.5µm (PM2.5) exposure and insulin resistance/type 2 diabetes mellitus. A role for innate immune cell activation has been suggested in the pathogenesis of these effects. We evaluated the role of CCR2 in PM2.5-mediated inflammation and insulin resistance. Wild-type C57BL/6 and CCR2-/- male mice were fed a high-fat diet and assigned to concentrated ambient PM2.5 or filtered air for 17 weeks via a whole body exposure system. PM2.5 exposure resulted in whole body insulin resistance and increased hepatic lipid accumulation in the liver which was attenuated in CCR2-/- mice by inhibiting SREBP1c mediated transcriptional programming, decreasing fatty acid uptake and p38 (but not JNK/ERK) MAPK activity. CCR2-/- restored abnormal phosphorylation levels of AKT, AMPK in visceral adipose tissue and adipose tissue macrophage content. However, the impaired whole body glucose tolerance and reduced GLUT4 in skeletal muscle in response to PM2.5 was not corrected by CCR2 deficiency. CCR2 modulates PM2.5-mediated insulin resistance by regulating visceral adipose tissue inflammation and hepatic lipid metabolism. These findings provide new mechanistic links between air pollution mediated insulin resistance and associated abnormalities in lipid metabolism and adipose inflammation.

Myostatin inhibition improves insulin signaling in muscles of mice with high fat diet‐induced diabetes

Myostatin inhibits skeletal muscle growth. Animals lacking myostatin develops significantly larger muscles, which are associated with reduced adiposity and lower blood glucose. We investigated whether myostatin inhibition would improve the metabolic profile of diabetic mice. C56/BL6 mice were fed a high fat diet (HFD) for 10 months. During the last 3 weeks, myostatin was inhibited by injections of a myostatin peptibody in mice on HFD vs PBS injected mice on a HFD. Body weight, lean mass and adipose tissue were quantified using an x‐ray imager; oxygen consumption and carbon dioxide production were measured using an animal monitoring system. Myostatin inhibition (MI) decreased blood glucose, serum insulin and increased glucose disposal in response to insulin. Also, there was increase in energy expenditure, associated with a decrease in the percent body fat plus a decrease in serum fatty acids. MI also increased p‐Akt in both muscle and white adipose tissue (WAT), responses linked to increased expression of fatty acid oxidation genes, plus an increase in AMPK activation plus expression of PPAR. We propose that myostatin, by suppressing both the AMPK and PPAR axes in skeletal muscle and adipose tissue interferes with insulin signaling and reduces fatty acid oxidation. In conclusion, targeting myostatin corrects these defects improving both insulin signaling and lipid metabolism in diabetes.

Lactobacillus rhamnosus GG improves insulin sensitivity and reduces adiposity in high-fat diet-fed mice through enhancement of adiponectin production

Recently, a probiotic Lactobacillus rhamnosus GG (LGG) has shown several beneficial effects, including improved insulin sensitivity. To clarify the mechanism underlying the insulin-sensitizing effect of LGG, mice were orally administrated with LGG for 13 weeks, and their body weight, insulin sensitivity, and expression of genes related to glucose and lipid metabolism were examined. LGG-treated mice showed attenuated weight gain and enhanced insulin sensitivity in high fat diet group, while no change was observed in normal diet-fed group. The expression of fatty acid oxidative genes in the liver was increased and gluconeogenic genes were decreased. GLUT4 mRNA expression in skeletal muscle and adiponectin production in adipose tissue were significantly increased. This was corroborated with the increased activation of AMPK in skeletal muscle and adipose tissue. Taken together, these results indicate that LGG treatment improves insulin sensitivity and reduces lipid accumulation by stimulating adiponectin secretion and consequent activation of AMPK.

Ghrelin and cannabinoids require the ghrelin receptor to affect cellular energy metabolism

IntroductionGhrelin is a potent orexigenic brain-gut peptide with lipogenic and diabetogenic effects, possibly mediated by growth hormone secretagogue receptor (GHS-R1a). Cannabinoids also have orexigenic and lipogenic effects. AMPK is a regulator of energy homeostasis and we have previously shown that ghrelin and cannabinoids stimulate hypothalamic AMPK activity while inhibiting it in the liver and adipose tissue, suggesting that AMPK mediates both the central appetite-inducing and peripheral effects of ghrelin and cannabinoids. AimsUsing GHS-R KO mice, we investigated whether the known ghrelin receptor GHS-R1a is required for the tissue-specific effects of ghrelin on AMPK activity, and if an intact ghrelin signalling pathway is necessary for the effects of cannabinoids on AMPK activity. MethodsWild-type and GHS-R KO mice were treated intraperitoneally with ghrelin 500ng/g bodyweight or CB1 agonist HU210 20ng/g and hypothalamic, hepatic and adipose AMPK activity was studied using a functional kinase assay. ResultsGhrelin and HU210 significantly stimulated hypothalamic AMPK activity in wild-type animals (mean±SEM, 122.5±5.2% and 128±11.6% of control, p<0.05) and inhibited it in liver (55.1±4.8% and 62.2±14.5%, p<0.01) and visceral fat (mesenteric fat (MF): 54.6±16% and 52.0±9.3%, p<0.05; epididymal fat (EF): 47.9±12.1% and 45.6±1.7%, p<0.05). The effects of ghrelin, and interestingly also HU210, on hypothalamic, visceral fat and liver AMPK activity were abolished in the GHS-R KO mice (hypothalamus: 107.9±7.7% and 87.4±13.3%, liver: 100.5±11.6% and 116.7±5.4%, MF: 132.1±29.9% and 107.1±32.7%, EF: 89.8±7.3% and 91.7±18.3%, p>0.05). ConclusionsGhrelin requires GHS-R1a for its effect on hypothalamic, liver and adipose tissue AMPK activity. An intact ghrelin signalling pathway is necessary for the effects of cannabinoids on AMPK activity.

Effects of Exercise on the Regulation and Function of AMPK in Adipose Tissue

Effects of Exercise on the Regulation and Function of AMPK in Adipose Tissue