Niemann-Pick C1-Like 1 deletion in mice prevents high-fat diet-induced fatty liver by reducing lipogenesis

Niemann-Pick C1-Like 1 (NPC1L1) mediates intestinal absorption of dietary and biliary cholesterol. Ezetimibe, by inhibiting NPC1L1 function, is widely used to treat hypercholesterolemia in humans. Interestingly, ezetimibe treatment appears to attenuate hepatic steatosis in rodents and humans without a defined mechanism. Overconsumption of a high-fat diet (HFD) represents a major cause of metabolic disorders including fatty liver. To determine whether and how NPC1L1 deficiency prevents HFD-induced hepatic steatosis, in this study, we fed NPC1L1 knockout (L1-KO) mice and their wild-type (WT) controls an HFD, and found that 24 weeks of HFD feeding causes no fatty liver in L1-KO mice. Hepatic fatty acid synthesis and levels of mRNAs for lipogenic genes are substantially reduced but hepatic lipoprotein-triglyceride production, fatty acid oxidation, and triglyceride hydrolysis remain unaltered in L1-KO versus WT mice. Strikingly, L1-KO mice are completely protected against HFD-induced hyperinsulinemia under both fed and fasted states and during glucose challenge. Despite similar glucose tolerance, L1-KO relative WT mice are more insulin sensitive and in the overnight-fasted state display significantly lower plasma glucose concentrations. In conclusion, NPC1L1 deficiency in mice prevents HFD-induced fatty liver by reducing hepatic lipogenesis, at least in part, through attenuating HFD-induced insulin resistance, a state known to drive hepatic lipogenesis through elevated circulating insulin levels.     

Adipose Overexpression of Heme Oxygenase-1 Does Not Protect against High Fat Diet-Induced Insulin Resistance in Mice

Heme oxygenase-1 (HO-1) is a stress-responsive enzyme with potent anti-oxidant and anti-inflammatory activities. Previous studies have shown that systemic induction of HO-1 by chemical inducers reduces adiposity and improves insulin sensitivity. To dissect the specific function of HO-1 in adipose tissue, we generated transgenic mice with adipose HO-1 overexpression using the adipocyte-specific aP2 promoter. The transgenic (Tg) mice exhibit similar metabolic phenotype as wild type (WT) control under chow-fed condition. High fat diet (HFD) challenge significantly increased the body weights of WT and Tg mice to a similar extent. Likewise, HFD-induced glucose intolerance and insulin resistance were not much different between WT and Tg mice. Analysis of the adipose tissue gene expression revealed that the mRNA levels of adiponectin and interleukin-10 were significantly higher in chow diet-fed Tg mice as compared to WT counterparts, whereas HFD induced downregulation of adiponectin gene expression in both Tg and WT mice to a similar level. HFD-induced proinflammatory cytokine expression in adipose tissues were comparable between WT and transgenic mice. Nevertheless, immunohistochemistry and gene expression analysis showed that the number of infiltrating macrophages with preferential expression of M2 markers was significantly higher in the adipose tissue of obese Tg mice than WT mice. Further experiment demonstrated that myeloid cells from Tg mice expressed higher level of HO-1 and exhibited greater migration response toward chemoattractant in vitro. Collectively, these data indicate that HO-1 overexpression in adipocytes does not protect against HFD-induced obesity and the development of insulin resistance in mice.     

Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet

Free fatty acid receptor 2 (Ffar2), also known as GPR43, is activated by short-chain fatty acids (SCFA) and expressed in intestine, adipocytes, and immune cells, suggesting involvement in lipid and immune regulation. In the present study, Ffar2-deficient mice (Ffar2-KO) were given a high-fat diet (HFD) or chow diet and studied with respect to lipid and energy metabolism. On a HFD, Ffar2-KO mice had lower body fat mass and increased lean body mass. The changed body composition was accompanied by improved glucose control and lower HOMA index, indicating improved insulin sensitivity in Ffar2-KO mice. Moreover, the Ffar2-KO mice had higher energy expenditure accompanied by higher core body temperature and increased food intake. The liver weight and content of triglycerides as well as plasma levels of cholesterol were lower in the Ffar2-KO mice fed a HFD. A histological examination unveiled decreased lipid interspersed in brown adipose tissue of the Ffar2-KO mice. Interestingly, no significant differences in white adipose tissue (WAT) cell size were observed, but significantly lower macrophage content was detected in WAT from HFD-fed Ffar2-KO compared with wild-type mice. In conclusion, Ffar2 deficiency protects from HFD-induced obesity and dyslipidemia at least partly via increased energy expenditure.     

Mice lacking myotubularin-related protein 14 show accelerated high-fat diet-induced lipid accumulation and inflammation

The phosphoinositide phosphatase, myotubularin-related protein 14 (MTMR14), has been reported to play an important role in the regulation of muscle performance, autophagy, and aging in mice. We previously showed that MTMR14-knockout (KO) mice gain weight earlier than their wild-type (WT) littermates even on a normal chow diet (NCD), suggesting that this gene might also be involved in regulating metabolism. In the present study, we evaluated the effect of MTMR14 deficiency on high-fat diet (HFD)-induced obesity, lipid accumulation, metabolic disorders, and inflammation in WT and MTMR14-KO mice fed with NCD or HFD. To this end, MTMR14-KO mice fed with HFD showed significantly increased body weight, blood glucose levels, serum triglyceride (TG) levels, and total cholesterol (TC) levels as compared to their age-matched WT control. Additionally, lipid accumulation also increased in the KO mice. Simultaneously, the expression of metabolism-associated genes (Glut4, adiponectin, and leptin) was different in the liver, muscle, and fatty tissue of MTMR14-KO mice fed with HFD. More importantly, the expression of several inflammation-associated genes (TNF-α, IL-6, IL-1β, and MCP-1) dramatically increased in the liver, muscle, and fatty tissue of MTMR14-KO mice relative to control. Taken together, these results suggest that MTMR14 deficiency accelerates HFD-induced metabolic dysfunction and inflammation. Furthermore, the results showed that exacerbated metabolic dysfunction and inflammation may be regulated via the PI3K/Akt and ERK signaling pathways.     

Osteopontin is required for the early onset of high fat diet-induced insulin resistance in mice

Background

Insulin resistance is manifested in muscle, adipose tissue, and liver and is associated with adipose tissue inflammation. The cellular components and mechanisms that regulate the onset of diet-induced insulin resistance are not clearly defined.

Methodology and Principal Findings

We initially observed osteopontin (OPN) mRNA over-expression in adipose tissue of obese, insulin resistant humans and rats which was normalized by thiazolidinedione (TZD) treatment in both species. OPN regulates inflammation and is implicated in pathogenic maladies resulting from chronic obesity. Thus, we tested the hypothesis that OPN is involved in the early development of insulin resistance using a 2–4 week high fat diet (HFD) model. OPN KO mice fed HFD for 2 weeks were completely protected from the severe skeletal muscle, liver and adipose tissue insulin resistance that developed in wild type (WT) controls, as determined by hyperinsulinemic euglycemic clamp and acute insulin-stimulation studies. Although two-week HFD did not alter body weight or plasma free fatty acids and cytokines in either strain, HFD-induced hyperleptinemia, increased adipose tissue inflammation (macrophages and cytokines), and adipocyte hypertrophy were significant in WT mice and blunted or absent in OPN KO mice. Adipose tissue OPN protein isoform expression was significantly altered in 2- and 4-week HFD-fed WT mice but total OPN protein was unchanged. OPN KO bone marrow stromal cells were more osteogenic and less adipogenic than WT cells in vitro. Interestingly, the two differentiation pathways were inversely affected by HFD in WT cells in vitro.

Conclusions

The OPN KO phenotypes we report reflect protection from insulin resistance that is associated with changes in adipocyte biology and adipose tissue inflammatory status. OPN is a key component in the development of HFD-induced insulin resistance.     

Anti-obesity properties of a Sasa quelpaertensis extract in high-fat diet-induced obese mice

This study explores the anti-obesity properties of a Sasa quelpaertensis leaf extract (SQE) in high-fat diet (HFD)-induced obese C57BL/6 mice and mature 3T3-L1 adipocytes. SQE administration with HFD for 70 d significantly decreased the body weight gain, adipose tissue weight, and serum total cholesterol and triglyceride levels in comparison with the HFD group. SQE administration also reduced the serum levels of glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and lactate dehydrogenase, and the accumulation of lipid droplets in the liver, suggesting a protective effect against HFD-induced hepatic steatosis. SQE administration restored the HFD-induced decreases with phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in epididymal adipose tissue. SQE also induced AMPK phosphorylation in mature 3T3-L1 adipocytes. These results suggest that SQE exerted an anti-obesity effect on HFD-induced obese mice by activating AMPK in adipose tissue and reducing lipid droplet accumulation in the liver.     

Inhibition of high-fat diet–induced obesity via reduction of ER-resident protein Nogo occurs through multiple mechanisms

Obesity is a risk factor for insulin resistance, type 2 diabetes, and cardiovascular diseases. Reticulon-4 (Nogo) is an endoplasmic reticulum–resident protein with unclear functions in obesity. Herein, we investigated the effect of Nogo on obesity and associated metabolic disorders. Human serum samples were collected to explore the relationship between circulating Nogo-B and body mass index value. Nogo-deficient and WT littermate control mice were fed normal chow or high-fat diet (HFD) for 14 weeks, and HFD-induced obese C57BL/6J mice were injected scrambled or Nogo siRNA for 2 weeks. We found that in human and mouse serum, Nogo-B was positively correlated to body mass index/bodyweight and lipid profiles. Reduced Nogo (by genetic deletion or siRNA transfection) protected mice against HFD-induced obesity and related metabolic disorders. We demonstrate that Nogo deficiency reversed HFD-induced whitening of brown adipose tissue, thereby increasing thermogenesis. It also ameliorated lipid accumulation in tissues by activating the adiponectin–adiponectin receptor 1–AMP-activated kinase α signaling axis. Finally, Nogo deficiency potently reduced HFD-induced serum proinflammatory cytokines and infiltration of macrophages into metabolic organs, which is related to enhanced NF-κB p65 degradation via the lysosome pathway. Collectively, our study suggests that reduced levels of Nogo protect mice against HFD-induced obesity by increasing thermogenesis and energy metabolism while inhibiting NF-κB-mediated inflammation. Our results indicate that inhibition of Nogo may be a potential strategy for obesity treatment.     

Adipose monocyte chemotactic protein-1 deficiency reduces high-fat diet-enhanced mammary tumorigenesis in MMTV-PyMT mice

Monocyte chemotactic protein-1 (MCP-1) is an adipokine with demonstrated carcinogenic potential. However, there is a lack of evidence whether adipose-produced MCP-1 contributes to breast cancer. We tested the hypothesis that adipose-produced MCP-1 contributes to mammary tumorigenesis in this study. In a breast cancer model of mouse mammary tumor virus-polyomavirus middle T-antigen (MMTV-PyMT), mice with or without adipose MCP-1 knockout [designated as Mcp-1^−/− or wild-type (WT)] were fed the standard AIN93G diet (16% of energy from soybean oil) or a high-fat diet (HFD, 45% of energy from soybean oil). Adipose MCP-1 knockout reduced Mcp-1 expression in adipose tissue and concentrations of MCP-1 in plasma. Mcp-1^−/− mice fed the HFD had less body fat than their WT counterparts. Adipose MCP-1 knockout attenuated HFD-enhanced mammary tumorigenesis, evidenced by lower mammary tumor volume. Furthermore, Mcp-1^−/− mice, regardless of diet, had a longer tumor latency and less tumor weight than WT mice. When fed the HFD, Mcp-1^−/− mice, compared to WT mice, exhibited lower concentrations of insulin, leptin, resistin, vascular endothelial growth factor and hepatic growth factor in plasma. In summary, adipose MCP-1 deficiency attenuated HFD-enhanced MMTV-PyMT mammary tumorigenesis. This attenuation can be attributed to less body adiposity, improvement in insulin sensitivity and down-regulation in protumorigenic inflammation cytokines and angiogenic factors in Mcp-1^−/− mice. It concludes that adipose-produced MCP-1 contributes to mammary tumorigenesis in the MMTV-PyMT mouse model.     

GPR105 Ablation Prevents Inflammation and Improves Insulin Sensitivity in Mice with Diet-Induced Obesity

GPR105, a G protein-coupled receptor for UDP-glucose, is highly expressed in several human tissues and participates in the innate immune response. Because inflammation has been implicated as a key initial trigger for type 2 diabetes, we hypothesized that GPR105 (official gene name: P2RY14) might play a role in the initiation of inflammation and insulin resistance in obesity. To this end, we investigated glucose metabolism in GPR105 knockout (KO) and wild-type (WT) mice fed a high-fat diet (HFD). We also examined whether GPR105 regulates macrophage recruitment to liver or adipose tissues by in vivo monocyte tracking and in vitro chemotaxis experiments, followed by transplantation of bone marrow from either KO or WT donors to WT recipients. Our data show that genetic deletion of GPR105 confers protection against HFD-induced insulin resistance, with reduced macrophage infiltration and inflammation in liver, and increased insulin-stimulated Akt phosphorylation in liver, muscle, and adipose tissue. By tracking monocytes from either KO or WT donors, we found that fewer KO monocytes were recruited to the liver of WT recipients. Furthermore, we observed that uridine 5-diphosphoglucose enhanced the in vitro migration of bone marrow-derived macrophages from WT but not KO mice, and that plasma uridine 5-diphosphoglucose levels were significantly higher in obese versus lean mice. Finally, we confirmed that insulin sensitivity improved in HFD mice with a myeloid cell-specific deletion of GPR105. These studies indicate that GPR105 ablation mitigates HFD-induced insulin resistance by inhibiting macrophage recruitment and tissue inflammation. Hence GPR105 provides a novel link between innate immunity and metabolism.     

12/15-Lipoxygenase Is Required for the Early Onset of High Fat Diet-Induced Adipose Tissue Inflammation and Insulin Resistance in Mice

Background

Recent understanding that insulin resistance is an inflammatory condition necessitates searching for genes that regulate inflammation in insulin sensitive tissues. 12/15-lipoxygenase (12/15LO) regulates the expression of proinflammatory cytokines and chemokines and is implicated in the early development of diet-induced atherosclerosis. Thus, we tested the hypothesis that 12/15LO is involved in the onset of high fat diet (HFD)-induced insulin resistance.

Methodology/Principal Findings

Cells over-expressing 12/15LO secreted two potent chemokines, MCP-1 and osteopontin, implicated in the development of insulin resistance. We assessed adipose tissue inflammation and whole body insulin resistance in wild type (WT) and 12/15LO knockout (KO) mice after 2–4 weeks on HFD. In adipose tissue from WT mice, HFD resulted in recruitment of CD11b⁺, F4/80⁺ macrophages and elevated protein levels of the inflammatory markers IL-1β, IL-6, IL-10, IL-12, IFNγ, Cxcl1 and TNFα. Remarkably, adipose tissue from HFD-fed 12/15LO KO mice was not infiltrated by macrophages and did not display any increase in the inflammatory markers compared to adipose tissue from normal chow-fed mice. WT mice developed severe whole body (hepatic and skeletal muscle) insulin resistance after HFD, as measured by hyperinsulinemic euglycemic clamp. In contrast, 12/15LO KO mice exhibited no HFD-induced change in insulin-stimulated glucose disposal rate or hepatic glucose output during clamp studies. Insulin-stimulated Akt phosphorylation in muscle tissue from HFD-fed mice was significantly greater in 12/15LO KO mice than in WT mice.

Conclusions

These results demonstrate that 12/15LO mediates early stages of adipose tissue inflammation and whole body insulin resistance induced by high fat feeding.     

Angiotensin type 1 receptor modulates macrophage polarization and renal injury in obesity

The mechanisms for increased risk of chronic kidney disease (CKD) in obesity remain unclear. The renin-angiotensin system is implicated in the pathogenesis of both adiposity and CKD. We investigated whether the angiotensin type 1 (AT(1)) receptor, composed of dominant AT(1a) and less expressed AT(1b) in wild-type (WT) mice, modulates development and progression of kidney injury in a high-fat diet (HFD)-induced obesity model. WT mice had increased body weight, body fat, and insulin levels and decreased adiponectin levels after 24 wk of a high-fat diet. Identically fed AT(1a) knockout (AT1aKO) mice gained weight similarly to WT mice, but had lower body fat and higher plasma cholesterol. Both obese AT1aKO and obese WT mice had increased visceral fat and kidney macrophage infiltration, with more proinflammatory M1 macrophage markers as well as increased mesangial expansion and tubular vacuolization, compared with lean mice. These abnormalities were heightened in the obese AT1aKO mice, with downregulated M2 macrophage markers and increased macrophage AT(1b) receptor. Treatment with an AT(1) receptor blocker, which affects both AT(1a) and AT(1b), abolished renal macrophage infiltration with inhibition of renal M1 and upregulation of M2 macrophage markers in obese WT mice. Our data suggest obesity accelerates kidney injury, linked to augmented inflammation in adipose and kidney tissues and a proinflammatory shift in macrophage and M1/M2 balance.     

The role of GM-CSF in adipose tissue inflammation

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine that has a central action to reduce food intake and body weight. Consistent with this, GM-CSF knockout mice are more obese and hyperphagic than wild-type mice. However, in lung, GM-CSF is an important determinant of macrophage infiltration. Consequently, we sought to determine if GM-CSF might contribute to adipose tissue macrophage accumulation, insulin resistance, and low-grade inflammation that occurs when animals gain weight on a high-fat diet (HFD). We therefore determined how targeted genetic disruption of GM-CSF can affect adipose tissue macrophage and cytokine gene expression as well as glucose homeostasis by performing hyperinsulinemic-euglycemic clamps. The number of macrophages and CCR2 gene expression in adipose tissue of GM-CSF knockout mice was decreased relative to those in wild-type mice, and the adipocyte size of mesenteric fat was increased in GM-CSF knockout mice on a HFD compared with wild-type mice. The level of mRNA of the proinflammatory cytokines interleukin-1beta, tumor necrosis factor-alpha, and macrophage inflammatory protein-1alpha was significantly lower in mesenteric fat of GM-CSF knockout mice on the HFD than in wild-type mice. Using the hyperinsulinemic-euglycemic clamp technique, GM-CSF knockout mice had greater overall insulin sensitivity. This increase was due to enhanced peripheral uptake and utilization of glucose rather than to increased hepatic insulin sensitivity. Collectively, the data suggest that the GM-CSF knockout mutation ameliorates peripheral insulin resistance in spite of increased adiposity by reducing inflammation in adipose tissue in response to a HFD.     

Influence of high-fat diet on amine oxidase activity in white adipose tissue of mice prone or resistant to diet-induced obesity

Decreased monoamine oxidase (MAO) activity has been observed in adipose tissue of obese patients. Since substrates of MAO and semicarbazide-sensitive amine oxidase (SSAO) can modify adipocyte metabolism, this work investigates whether changes in amine oxidase activity may occur during white adipose tissue (WAT) development. We evaluated MAO and SSAO activities in WAT of high-fat diet (HFD) and low-fat diet fed mice. To distinguish the effect of HFD on its own from the effect of fat mass enlargement, obesity-prone transgenic line of the FVBn strain lacking beta3-adrenergic receptors (AR) but expressing human beta3-AR and alpha2-AR (mbeta3-/-, hbeta3+/+, halpha2+/-) was compared to its obesity-resistant control (mbeta3-/-, hbeta3+/+). As already reported, the former mice became obese while the latter resisted to HFD. No significant change in SSAO or MAO activity was found in WAT of both strains after HFD when expressing oxidase activity per milligram of protein. However, when considering the overall capacity of the fat depots to oxidize tyramine or benzylamine, there was an increase in MAO and SSAO activity only in the enlarged WAT of HFD-induced obese mice. Therefore, the comparison of these models allowed to demonstrate that the higher amine oxidase capacity hold in enlarged fat stores of obese mice is more likely the consequence of increased fat cell number rather than the result of an increased expression of MAO or SSAO in the adipocyte.     

Momordica charantia (Bitter Melon) Reduces Obesity-Associated Macrophage and Mast Cell Infiltration as well as Inflammatory Cytokine Expression in Adipose Tissues

Obesity is a world-wide epidemic disease that correlates closely with type 2 diabetes and cardiovascular diseases. Obesity-induced chronic adipose tissue inflammation is now considered as a critical contributor to the above complications. Momordica charantia (bitter melon, BM) is a traditional Chinese food and well known for its function of reducing body weight gain and insulin resistance. However, it is unclear whether BM could alleviate adipose tissue inflammation caused by obesity. In this study, C57BL/6 mice were fed high fat diet (HFD) with or without BM for 12 weeks. BM-contained diets ameliorated HFD-induced obesity and insulin resistance. Histological and real-time PCR analysis demonstrated BM not only reduced macrophage infiltration into epididymal adipose tissues (EAT) and brown adipose tissues (BAT). Flow cytometry show that BM could modify the M1/M2 phenotype ratio of macrophages in EAT. Further study showed that BM lowered mast cell recruitments in EAT, and depressed pro-inflammatory cytokine monocyte chemotactic protein-1 (MCP-1) expression in EAT and BAT as well as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) expression in EAT. Finally, ELISA analysis showed BM-contained diets also normalized serum levels of the cytokines. In summary, in concert with ameliorated insulin resistance and fat deposition, BM reduced adipose tissue inflammation in diet-induced obese (DIO) mice.     

Raspberry promotes brown and beige adipocyte development in mice fed high-fat diet through activation of AMP-activated protein kinase (AMPK) α1

Development of brown and beige/brite adipocytes increases thermogenesis and helps to reduce obesity and metabolic syndrome. Our previous study suggests that dietary raspberry can ameliorate metabolic syndromes in diet-induced obese mice. Here, we further evaluated the effects of raspberry on energy expenditure and adaptive thermogenesis and determined whether these effects were mediated by AMP-activated protein kinase (AMPK). Mice deficient in the catalytic subunit of AMPKα1 and wild-type (WT) mice were fed a high-fat diet (HFD) or HFD supplemented with 5% raspberry (RAS) for 10 weeks. The thermogenic program and related regulatory factors in adipose tissue were assessed. RAS improved the insulin sensitivity and reduced fat mass in WT mice but not in AMPKα1^-/- mice. In the absence of AMPKα1, RAS failed to increase oxygen consumption and heat production. Consistent with this, the thermogenic gene expression in brown adipose tissue and brown-like adipocyte formation in subcutaneous adipose tissue were not induced by RAS in AMPKα1^-/- mice. In conclusion, AMPKα1 is indispensable for the effects of RAS on brown and beige/brite adipocyte development, and prevention of obesity and metabolic dysfunction.     

Kefir prevented excess fat accumulation in diet-induced obese mice

Excessive body fat accumulation can result in obesity, which is a serious health concern. Kefir, a probiotic, has recently shown possible health benefits in fighting obesity. This study investigated the inhibitory effects of 0.1 and 0.2% kefir powder on fat accumulation in adipose and liver tissues of high-fat diet (HFD)-induced obese mice. Kefir reduced body weight and epididymal fat pad weight and decreased adipocyte diameters in HFD-induced obese mice. This was supported by decreased expression of genes related to adipogenesis and lipogenesis as well as reduced proinflammatory marker levels in epididymal fat. Along with reduced hepatic triacylglycerol concentrations and serum alanine transaminase and aspartate transaminase activities, genes related to lipogenesis and fatty acid oxidation were downregulated and upregulated, respectively, in liver tissue. Kefir also decreased serum triacylglycerol, total cholesterol, and low-density lipoprotein–cholesterol concentrations. Overall, kefir has the potential to prevent obesity.     

Retinoic acid ameliorates high-fat diet-induced liver steatosis through Sirt1

In this study, treatment of C57 BL/6 J(wild type, WT) mice fed a high-fat diet(HFD) with retinoic acid(RA) decreased body weight and subcutaneous and visceral fat content, reversed the apparent hepatosteatosis, and reduced hepatic intracellular triglyceride and serum alanine transaminase(ALT) and aspartate aminotransferase(AST) concentrations. Moreover, RA treatment improved glucose tolerance and insulin sensitivity in WT mice fed a HFD. However, these RA-induced effects in WT mice fed a HFD were alleviated in liver specific Sirtuin 1(Sirt1) deficient(LKO) mice fed a HFD. Furthermore,RA also could not improve glucose tolerance and insulin sensitivity in LKO mice fed a HFD. The mechanism studies indicated that RA indeed increased the expression of hepatic Sirt1 and superoxide dismutase 2(Sod2), and inhibited the expression of sterol regulatory element binding protein 1 c(Srebp-1 c) in WT mice in vivo and in vitro. RA decreased mitochondrial reactive oxygen species(ROS) production in WT primary hepatocytes and increased mitochondrial DNA(mtDNA) copy number in WT mice liver. However, these RA-mediated molecular effects were also abolished in the liver and primary hepatocytes from LKO mice. In summary, RA protected against HFD-induced hepato steatosis by decreasing Srebp-1 c expression and improving antioxidant capacity through a Sirtl-mediated mechanism.     

GPNMB plays a protective role against obesity-related metabolic disorders by reducing macrophage inflammatory capacity

Obesity is a global health problem that is often related to cardiovascular and metabolic diseases. Chronic low-grade inflammation in white adipose tissue (WAT) is a hallmark of obesity. Previously, during a search for differentially expressed genes in WAT of obese mice, we identified glycoprotein nonmetastatic melanoma protein B (GPNMB), of which expression was robustly induced in pathologically expanded WAT. Here, we investigated the role of GPNMB in obesity-related metabolic disorders utilizing GPNMB-deficient mice. When fed a high-fat diet (HFD), GPNMB-deficient mice showed body weight and adiposity similar to those of wild-type (WT) mice. Nonetheless, insulin and glucose tolerance tests revealed significant obesity-related metabolic disorders in GPNMB-KO mice compared with WT mice fed with HFD. Chronic WAT inflammation was remarkably worsened in HFD-fed GPNMB-KO mice, accompanied by a striking increase in crown-like structures, typical hallmarks for diseased WAT. Macrophages isolated from GPNMB-KO mice were observed to produce more inflammatory cytokines than those of WT mice, a difference abolished by supplementation with recombinant soluble GPNMB extracellular domain. We demonstrated that GPNMB reduced the inflammatory capacity of macrophages by inhibiting NF-κB signaling largely through binding to CD44. Finally, we showed that macrophage depletion by addition of clodronate liposomes abolished the worsened WAT inflammation and abrogated the exacerbation of metabolic disorders in GPNMB-deficient mice fed on HFD. Our data reveal that GPNMB negatively regulates macrophage inflammatory capacities and ameliorates the WAT inflammation in obesity; therefore we conclude that GPNMB is a promising therapeutic target for the treatment of metabolic disorders associated with obesity.     

The Gustatory Signaling Pathway and Bitter Taste Receptors Affect the Development of Obesity and Adipocyte Metabolism in Mice

Intestinal chemosensory signaling pathways involving the gustatory G-protein, gustducin, and bitter taste receptors (TAS2R) have been implicated in gut hormone release. Alterations in gut hormone profiles may contribute to the success of bariatric surgery. This study investigated the involvement of the gustatory signaling pathway in the development of diet-induced obesity and the therapeutic potential of targeting TAS2Rs to induce body weight loss. α-gustducin-deficient (α-gust^-/-) mice became less obese than wild type (WT) mice when fed a high-fat diet (HFD). White adipose tissue (WAT) mass was lower in α-gust^-/- mice due to increased heat production as a result of increases in brown adipose tissue (BAT) thermogenic activity, involving increased protein expression of uncoupling protein 1. Intra-gastric treatment of obese WT and α-gust^-/- mice with the bitter agonists denatonium benzoate (DB) or quinine (Q) during 4 weeks resulted in an α-gustducin-dependent decrease in body weight gain associated with a decrease in food intake (DB), but not involving major changes in gut peptide release. Both WAT and 3T3-F442A pre-adipocytes express TAS2Rs. Treatment of pre-adipocytes with DB or Q decreased differentiation into mature adipocytes. In conclusion, interfering with the gustatory signaling pathway protects against the development of HFD-induced obesity presumably through promoting BAT activity. Intra-gastric bitter treatment inhibits weight gain, possibly by directly affecting adipocyte metabolism.