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.     

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.     

Genetic disruption of protein phosphatase 5 in mice prevents high-fat diet feeding-induced weight gain

The role of serine/threonine protein phosphatase 5 (PP5) in the development of obesity and insulin resistance associated with high-fat diet-feeding (HFD) was examined using PP5-deficient mice (Ppp5c^−/−). Despite similar caloric intake, Ppp5c^−/− mice on HFD gained markedly less weight and did not accumulate visceral fat compared to wild-type littermates (Ppp5c^+/+). On a control diet, Ppp5c^−/− mice had markedly improved glucose control compared to Ppp5c^+/+ mice, an effect diminished by HFD. However, even after 10 weeks of HFD glucose control in Ppp5c^−/− mice was similar to that observed in Ppp5c^+/+ mice on the control diet. Thus, PP5 deficiency confers protection against HFD-induced weight gain in mice.     

The essential function of CARD9 in diet‐induced inflammation and metabolic disorders in mice

Inflammation and metabolic disorder are common pathophysiological conditions, which play a vital role in the development of obesity and type 2 diabetes. The purpose of this study was to explore the effects of caspase recruitment domain (CARD) 9 in the high fat diet (HFD)‐treated mice and attempt to find a molecular therapeutic target for obesity development and treatment. Sixteen male CARD9^?/? and corresponding male WT mice were fed with normal diet or high fat diet, respectively, for 12 weeks. Glucose tolerance, insulin resistance, oxygen consumption and heat production of the mice were detected. The CARD9/MAPK pathway‐related gene and protein were determined in insulin‐responsive organs using Western blotting and quantitative PCR. The results showed that HFD‐induced insulin resistance and impairment of glucose tolerance were more severe in WT mice than that in the CARD9^?/? mice. CARD9 absence significantly modified O₂ consumption, CO₂ production and heat production. CARD9^?/? mice displayed the lower expression of p38 MAPK, JNK and ERK when compared to the WT mice in both HFD‐ and ND‐treated groups. HFD induced the increase of p38 MAPK, JNK and ERK in WT mice but not in the CARD9^?/? mice. The results indicated that CARD9 absence could be a vital protective factor in diet‐induced obesity via the CARD9/MAPK pathway, which may provide new insights into the development of gene knockout to improving diet‐induced obesity and metabolism disorder.     

Folic acid supplementation alters the DNA methylation profile and improves insulin resistance in high-fat-diet-fed mice

Folic acid (FA) supplementation may protect from obesity and insulin resistance, the effects and mechanism of FA on chronic high-fat-diet-induced obesity-related metabolic disorders are not well elucidated. We adopted a genome-wide approach to directly examine whether FA supplementation affects the DNA methylation profile of mouse adipose tissue and identify the functional consequences of these changes. Mice were fed a high-fat diet (HFD), normal diet (ND) or an HFD supplemented with folic acid (20 μg/ml in drinking water) for 10 weeks, epididymal fat was harvested, and genome-wide DNA methylation analyses were performed using methylated DNA immunoprecipitation sequencing (MeDIP-seq). Mice exposed to the HFD expanded their adipose mass, which was accompanied by a significant increase in circulating glucose and insulin levels. FA supplementation reduced the fat mass and serum glucose levels and improved insulin resistance in HFD-fed mice. MeDIP-seq revealed distribution of differentially methylated regions (DMRs) throughout the adipocyte genome, with more hypermethylated regions in HFD mice. Methylome profiling identified DMRs associated with 3787 annotated genes from HFD mice in response to FA supplementation. Pathway analyses showed novel DNA methylation changes in adipose genes associated with insulin secretion, pancreatic secretion and type 2 diabetes. The differential DNA methylation corresponded to changes in the adipose tissue gene expression of Adcy3 and Rapgef4 in mice exposed to a diet containing FA. FA supplementation improved insulin resistance, decreased the fat mass, and induced DNA methylation and gene expression changes in genes associated with obesity and insulin secretion in obese mice fed a HFD.     

Lectin-like oxidized low-density lipoprotein receptor-1 is required for the adipose tissue expression of proinflammatory cytokines in high-fat diet-induced obese mice

Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) is a receptor for oxidized LDL, and is strongly expressed in endothelial cells at an early stage of atherosclerosis. LOX-1 expression in adipocytes is induced by PPARγ (ligands and appears to be involved in adipocyte cholesterol metabolism. However, the role of adipose tissue LOX-1 in high-fat diet-induced obesity is unknown. We found that mRNA levels of adipose tissue LOX-1 were markedly increased in obese mice fed a high-fat diet (HFD) compared with those fed normal chow. The levels were closely correlated with those of a proinflammatory cytokine, monocyte chemoattractant protein-1 (MCP-1). Then, LOX-1 knockout (LOX-1-KO) and wild-type (WT) mice were fed HFD for 16 weeks. HFD feeding increased the body and mesenteric fat weights similarly in WT and LOX-1-KO mice. HFD-induced expressions of proinflammatory cytokines such as MCP-1, MIP-1α, and IL-6 were significantly less in LOX-1-KO than WT mice. Thus, LOX-1 is required for the HFD-induced expression of proinflammatory cytokines in the adipose tissue of obese mice.     

Involvement of the GHSR in the developmental programming and metabolic disturbances induced by maternal undernutrition

The mismatch between maternal undernutrition and adequate nutrition after birth increases the risk of developing metabolic diseases. We aimed to investigate whether the hyperghrelinemia during maternal undernourishment rewires the hypothalamic development of the offspring and contributes to the conversion to an obese phenotype when fed a high-fat diet (HFD). Pregnant C57BL/6 J, wild type (WT) and ghrelin receptor (GHSR)^−/− mice were assigned to either a normal nourished (NN) group, or an undernutrition (UN) (30% food restricted) group. All pups were fostered by NN Swiss mice. After weaning, pups were fed a normal diet, followed by a HFD from week 9. Plasma ghrelin levels peaked at postnatal day 15 (P15) in both C57BL/6 J UN and NN pups. Hypothalamic Ghsr mRNA expression was upregulated at P15 in UN pups compared to NN pups and inhibited agouti-related peptide (AgRP) projections. Adequate lactation increased body weight of UN WT but not of GHSR^−/− pups compared to NN littermates. After weaning with a HFD, body weight and food intake was higher in WT UN pups but lower in GHSR^−/− UN pups than in NN controls. The GHSR prevented a decrease in ambulatory activity and oxygen consumption in UN offspring during ad libitum feeding. Maternal undernutrition triggers developmental changes in the hypothalamus in utero which were further affected by adequate feeding after birth during the postnatal period by affecting GHSR signaling. The GHSR contributes to the hyperphagia and the increase in body weight when maternal undernutrition is followed by an obesity prone life environment.     

Maternal obesity induces gut inflammation and impairs gut epithelial barrier function in nonobese diabetic mice

Impairment of gut epithelial barrier function is a key predisposing factor for inflammatory bowel disease, type 1 diabetes (T1D) and related autoimmune diseases. We hypothesized that maternal obesity induces gut inflammation and impairs epithelial barrier function in the offspring of nonobese diabetic (NOD) mice. Four-week-old female NOD/ShiLtJ mice were fed with a control diet (CON; 10% energy from fat) or a high-fat diet (HFD; 60% energy from fat) for 8 weeks to induce obesity and then mated. During pregnancy and lactation, mice were maintained in their respective diets. After weaning, all offspring were fed the CON diet. At 16 weeks of age, female offspring were subjected to in vivo intestinal permeability test, and then ileum was sampled for biochemical analyses. Inflammasome mediators, activated caspase-1 and mature forms of interleukin (IL)-1β and IL-18 were enhanced in offspring of obese mothers, which was associated with elevated serum tumor necrosis factor α level and inflammatory mediators. Consistently, abundance of oxidative stress markers including catalase, peroxiredoxin-4 and superoxide dismutase 1 was heightened in offspring ileum (P<.05). Furthermore, offspring from obese mothers had a higher intestinal permeability. Morphologically, maternal obesity reduced villi/crypt ratio in the ileum of offspring gut. In conclusion, maternal obesity induced inflammation and impaired gut barrier function in offspring of NOD mice. The enhanced gut permeability in HFD offspring might predispose them to the development of T1D and other gut permeability-associated diseases.     

Long-Term Administration of High-Fat Diet Corrects Abnormal Bone Remodeling in the Tibiae of Interleukin-6-Deficient Mice

In this study, we aimed to evaluate the influence of diet-induced obesity on IL-6 deficiency-induced bone remodeling abnormality. Seven-week-old IL-6^-/- mice and their wild type (WT) littermates were fed a standard diet (SD) or high-fat diet (HFD) for 25 weeks. Lipid formation and bone metabolism in mice tibiae were investigated by histochemical analysis. Both IL-6^-/- and WT mice fed the HFD showed notable body weight gain, thickened cortical bones, and adipose accumulation in the bone marrow. Notably, the HFD normalized the bone phenotype of IL-6^-/- mice to that of their WT counterpart, as characterized by a decrease in bone mass and the presence of an obliquely arranged, plate-like morphology in the trabecular bone. Alkaline phosphatase and osteocalcin expressions were attenuated in both genotypes after HFD feeding, especially for the IL-6^-/- mice. Meanwhile, tartrate-resistant acid phosphatase staining was inhibited, osteoclast apoptosis rate down-regulated (revealed by TUNEL assay), and the proportion of cathepsin K (CK)-positive osteoclasts significantly increased in IL-6^-/- mice on a HFD as compared with IL-6^-/- mice on standard chow. Our results demonstrate that HFD-induced obesity reverses IL-6 deficiency-associated bone metabolic disorders by suppressing osteoblast activity, upregulating osteoclastic activity, and inhibiting osteoclast apoptosis.     

Ferulic acid maintains the self-renewal capacity of embryo stem cells and adipose-derived mesenchymal stem cells in high fat diet-induced obese mice

Self-renewal is required for embryo stem cells (ESCs) and adipose-derived mesenchymal stem cells (ADMSCs). This study examined the ability of ferulic acid in mouse ESCs and ADMSCs, in a high fat diet-induced mouse model. Initially, five natural compounds of ferulic acid, xanthohumol, curcumin, ascorbic acid, and quercetin were screened in ESCs using an alkaline phosphate ⁺(AP⁺) assay, as a self-renewal biomarker. A ferulic acid treatment was the highest AP⁺ staining in hop-hit screening compounds. Also a ferulic acid increased Nanog mRNA levels in ESCs. The in vivo effects of ferulic acid were next examined in an obese mouse model. C57BL/6 J male mice were fed either a high fat diet (HFD) or control diet with ferulic acid (5 g/kg diet) for 8 weeks. Ferulic acid exhibited weight loss and improved glucose homeostasis, lipid profiling, and hepatic steatosis in a HFD-induced mouse model. Next, ADMSCs (Sca-1⁺CD45⁻), a hallmark of fat stem cells, were then isolated and quantified from mouse abdominal adipose tissue. A HFD decreased the Sca-1⁺CD45⁻ cell population of ADMSCs, but HFD-induced obese mice given ferulic acid showed an increased the Sca-1⁺CD45⁻ cell population of ADMSCs. Moreover, ferulic acid enhanced NANOG mRNA levels in human ADMSCs and its related gene mRNA expression. Overall, this study suggests that ferulic acid preserves self-renewal in ESCs, and contributes to ADMSCs self-renewal and effective weight control in obesity.     

Taurine supplementation prevents morpho-physiological alterations in high-fat diet mice pancreatic β-cells

Taurine (Tau) is involved in beta (β)-cell function and insulin action regulation. Here, we verified the possible preventive effect of Tau in high-fat diet (HFD)-induced obesity and glucose intolerance and in the disruption of pancreatic β-cell morpho-physiology. Weaning Swiss mice were distributed into four groups: mice fed on HFD diet (36 % of saturated fat, HFD group); HTAU, mice fed on HFD diet and supplemented with 5 % Tau; control (CTL); and CTAU. After 19 weeks of diet and Tau treatments, glucose tolerance, insulin sensitivity and islet morpho-physiology were evaluated. HFD mice presented higher body weight and fat depots, and were hyperglycemic, hyperinsulinemic, glucose intolerant and insulin resistant. Their pancreatic islets secreted high levels of insulin in the presence of increasing glucose concentrations and 30 mM K⁺. Tau supplementation improved glucose tolerance and insulin sensitivity with a higher ratio of Akt phosphorylated (pAkt) related to Akt total protein content (pAkt/Akt) following insulin administration in the liver without altering body weight and fat deposition in HTAU mice. Isolated islets from HTAU mice released insulin similarly to CTL islets. HFD intake induced islet hypertrophy, increased β-cell/islet area and islet and β-cell mass content in the pancreas. Tau prevented islet and β-cell/islet area, and islet and β-cell mass alterations induced by HFD. The total insulin content in HFD islets was higher than that of CTL islets, and was not altered in HTAU islets. In conclusion, for the first time, we showed that Tau enhances liver Akt activation and prevents β-cell compensatory morpho-functional adaptations induced by HFD.     

Dietary sphingomyelin attenuates hepatic steatosis and adipose tissue inflammation in high-fat-diet-induced obese mice

Western-type diets can induce obesity and related conditions such as dyslipidemia, insulin resistance and hepatic steatosis. We evaluated the effects of milk sphingomyelin (SM) and egg SM on diet-induced obesity, the development of hepatic steatosis and adipose inflammation in C57BL/6J mice fed a high-fat, cholesterol-enriched diet for 10 weeks. Mice were fed a low-fat diet (10% kcal from fat) (n=10), a high-fat diet (60% kcal from fat) (HFD, n=14) or a high-fat diet modified to contain either 0.1% (w/w) milk SM (n=14) or 0.1% (w/w) egg SM (n=14). After 10 weeks, egg SM ameliorated weight gain, hypercholesterolemia and hyperglycemia induced by HFD. Both egg SM and milk SM attenuated hepatic steatosis development, with significantly lower hepatic triglycerides (TGs) and cholesterol relative to HFD. This reduction in hepatic steatosis was stronger with egg SM supplementation relative to milk SM. Reductions in hepatic TGs observed with dietary SM were associated with lower hepatic mRNA expression of PPARγ-related genes: Scd1 and Pparg2 in both SM groups, and Cd36 and Fabp4 with egg SM. Egg SM and, to a lesser extent, milk SM reduced inflammation and markers of macrophage infiltration in adipose tissue. Egg SM also reduced skeletal muscle TG content compared to HFD. Overall, the current study provides evidence of dietary SM improving metabolic complications associated with diet-induced obesity in mice. Further research is warranted to understand the differences in bioactivity observed between egg and milk SM.     

Human milk derived peptide AOPDM1 attenuates obesity by restricting adipogenic differentiation through MAPK signalling

BackgroundEmerging evidence revealed peptides within breast milk may be an abundant source of potential candidates for metabolism regulation. Our previous work identified numerous peptides existed in breast milk, but its function has not been validated. Thus, our study aims to screen for novel peptides that have the potential to antagonize obesity and diabetes.MethodsA function screen was designed to identify the candidate peptide and then the peptide effect was validated by assessing lipid storage. Afterwards, the in vivo study was performed in two obese models: high-fat diet (HFD)-induced obese mice and obese ob/ob mice. For mechanism study, a RNA-seq analysis was conducted to explore the pathway that account for the biological function of peptide.ResultsBy performing a small scale screening, a peptide (AVPVQALLLNQ) termed AOPDM1 (anti-obesity peptide derived from breast milk 1) was identified to reduce lipid storage in adipocytes. Further study showed AOPDM1 suppressed adipocyte differentiation by sustaining ERK activity at later stage of differentiation which down-regulated PPARγ expression. In vivo, AOPDM1 effectively reduced fat mass and improved glucose metabolism in high-fat diet (HFD)-induced obese mice and obese ob/ob mice.ConclusionsWe identified a novel peptide AOPDM1 derived from breast milk could restrict adipocyte differentiation and ameliorate obesity through regulating MAPK pathway.General significanceOur findings may provide a potential candidate for the discovery of therapeutic drugs for obesity and type 2 diabetes.     

CD38 deficiency suppresses adipogenesis and lipogenesis in adipose tissues through activating Sirt1/PPARγ signaling pathway

It has been recently reported that CD38 was highly expressed in adipose tissues from obese people and CD38‐deficient mice were resistant to high‐fat diet (HFD)‐induced obesity. However, the role of CD38 in the regulation of adipogenesis and lipogenesis is unknown. In this study, to explore the roles of CD38 in adipogenesis and lipogenesis in vivo and in vitro, obesity models were generated with male CD38^?/? and WT mice fed with HFD. The adipocyte differentiations were induced with MEFs from WT and CD38^?/? mice, 3T3‐L1 and C3H10T1/2 cells in vitro. The lipid accumulations and the alternations of CD38 and the genes involved in adipogenesis and lipogenesis were determined with the adipose tissues from the HFD‐fed mice or the MEFs, 3T3‐L1 and C3H10T1/2 cells during induction of adipocyte differentiation. The results showed that CD38^?/? male mice were significantly resistant to HFD‐induced obesity. CD38 expressions in adipocytes were significantly increased in WT mice fed with HFD, and the similar results were obtained from WT MEFs, 3T3‐L1 and C3H10T1/2 during induction of adipocyte differentiation. The expressions of PPARγ, AP2 and C/EBPα were markedly attenuated in adipocytes from HFD‐fed CD38^?/? mice and CD38^?/? MEFs at late stage of adipocyte differentiation. Moreover, the expressions of SREBP1 and FASN were also significantly decreased in CD38^?/? MEFs. Finally, the CD38 deficiency‐mediated activations of Sirt1 signalling were up‐regulated or down‐regulated by resveratrol and nicotinamide, respectively. These results suggest that CD38 deficiency impairs adipogenesis and lipogenesis through activating Sirt1/PPARγ‐FASN signalling pathway during the development of obesity.     

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.     

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.     

Increased Adiposity in Annexin A1-Deficient Mice

Production of Annexin A1 (ANXA1), a protein that mediates the anti-inflammatory action of glucocorticoids, is altered in obesity, but its role in modulation of adiposity has not yet been investigated. The objective of this study was to investigate modulation of ANXA1 in adipose tissue in murine models of obesity and to study the involvement of ANXA1 in diet-induced obesity in mice. Significant induction of ANXA1 mRNA was observed in adipose tissue of both C57BL6 and Balb/c mice with high fat diet (HFD)-induced obesity versus mice on chow diet. Upregulation of ANXA1 mRNA was independent of leptin or IL-6, as demonstrated by use of leptin-deficient ob/ob mice and IL-6 KO mice. Compared to WT mice, female Balb/c ANXA1 KO mice on HFD had increased adiposity, as indicated by significantly elevated body weight, fat mass, leptin levels, and adipocyte size. Whereas Balb/c WT mice upregulated expression of enzymes involved in the lipolytic pathway in response to HFD, this response was absent in ANXA1 KO mice. A significant increase in fasting glucose and insulin levels as well as development of insulin resistance was observed in ANXA1 KO mice on HFD compared to WT mice. Elevated plasma corticosterone levels and blunted downregulation of 11-beta hydroxysteroid dehydrogenase type 1 in adipose tissue was observed in ANXA1 KO mice compared to diet-matched WT mice. However, no differences between WT and KO mice on either chow or HFD were observed in expression of markers of adipose tissue inflammation.These data indicate that ANXA1 is an important modulator of adiposity in mice, with female ANXA1 KO mice on Balb/c background being more susceptible to weight gain and diet-induced insulin resistance compared to WT mice, without significant changes in inflammation.     

Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet

To determine whether long-term melanocortinergic activation can attenuate the metabolic effects of a high fat diet, mice overexpressing an NH(2)-terminal POMC transgene that includes alpha- and gamma(3)-MSH were studied on either a 10% low-fat diet (LFD) or 45% high-fat diet (HFD). Weight gain was modestly reduced in transgenic (Tg-MSH) male and female mice vs. wild type (WT) on HFD (P < 0.05) but not LFD. Substantial reductions in body fat percentage were found in both male and female Tg-MSH mice on LFD (P < 0.05) and were more pronounced on HFD (P < 0.001). These changes occurred in the absence of significant feeding differences in most groups, consistent with effects of Tg-MSH on energy expenditure and partitioning. This is supported by indirect calorimetry studies demonstrating higher resting oxygen consumption and lower RQ in Tg-MSH mice on the HFD. Tg-MSH mice had lower fasting insulin levels and improved glucose tolerance on both diets. Histological and biochemical analyses revealed that hepatic fat accumulation was markedly reduced in Tg-MSH mice on the HFD. Tg-MSH also attenuated the increase in corticosterone induced by the HFD. Higher levels of Agrp mRNA, which might counteract effects of the transgene, were measured in Tg-MSH mice on LFD (P = 0.02) but not HFD. These data show that long-term melanocortin activation reduces body weight, adiposity, and hepatic fat accumulation and improves glucose metabolism, particularly in the setting of diet-induced obesity. Our results suggest that long-term melanocortinergic activation could serve as a potential strategy for the treatment of obesity and its deleterious metabolic consequences.     

Latexin deficiency attenuates adipocyte differentiation and protects mice against obesity and metabolic disorders induced by high-fat diet

Obesity is a risk factor for many chronic diseases, and is associated with increased incidence rate of type 2 diabetes, hypertension, dyslipidemia and cardiovascular diseases. Adipocyte differentiation play critical role during development of obesity. Latexin (LXN), a mammalian carboxypeptidase inhibitor, plays important role in the proliferation and differentiation of stem cells, and highlights as a differentiation-associated gene that was significantly downregulated in prostate stem cells and whose expression increases through differentiation. However, it is unclear whether LXN is involved in adipocyte differentiation. The aim of this study was to evaluate the role of LXN on adipocyte differentiation, as well as its effects on high fat-induced obesity and metabolic disorders. In this study, we determine the expression of LXN in adipose tissue of lean and fat mice by Western blot, qPCR and immunohistochemistry. We found that LXN in fat tissues was continuous increased during the development of diet-induced obesity. We fed wild-type (WT) and LXN^−/−mice with high-fat diet (HFD) to study the effects of LXN on obesity and related metabolic functions. We found that mice deficient in LXN showed resistance against high-fat diet (HFD)-induced obesity, glucose tolerance, insulin tolerance and hepatic steatosis. In vitro studies indicated that LXN was highly induced during adipocyte differentiation, and positively regulated adipocyte differentiation and adipogenesis in 3T3-L1 cells and primary preadipocytes. Functional analysis revealed that the expression of LXN was positively regulated by mTOR/RXR/PPARɤ signaling pathway during the differentiation of adipocytes, while LXN deletion decreased the protein level of PPARɤ in adipocyte through enhancing FABP4 mediated ubiquitination, which led to impaired adipocyte differentiation and lipogenesis. Collectively, our data provide evidence that LXN is a key positive regulator of adipocyte differentiation, and therapeutics targeting LXN could be effective in preventing obesity and its associated disorders in clinical settings.Subject terms: Metabolic disorders, Mechanisms of disease