Brown Fat Dnmt3b Deficiency Ameliorates Obesity in Female Mice.
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ABSTRACT:
SUBMITTER: Li F
PROVIDER: S-EPMC8703316 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Increasing energy expenditure through activation of brown fat thermogenesis is a promising therapeutic strategy for the treatment of obesity. Epigenetic regulation has emerged as a key player in regulating brown fat development and thermogenic program. Here, we aimed to study the role of DNA methyltransferase 3b (Dnmt3b), a DNA methyltransferase involved in de novo DNA methylation, in the regulation of brown fat function and energy homeostasis. We generated a genetic model with Dnmt3b deletion in brown fat-skeletal lineage precursor cells (3bKO mice) by crossing Dnmt3b-floxed (fl/fl) mice with Myf5-Cre mice. Female 3bKO mice are prone to diet-induced obesity, which is associated with decreased energy expenditure. Dnmt3b deficiency also impairs cold-induced thermogenic program in brown fat. Surprisingly, further RNA-seq analysis reveals a profound up-regulation of myogenic markers in brown fat of 3bKO mice, suggesting a myocyte-like remodeling in brown fat. Further motif enrichment and pyrosequencing analysis suggests myocyte enhancer factor 2C (Mef2c) as a mediator for the myogenic alteration in Dnmt3b-deficient brown fat, as indicated by decreased methylation at its promoter. Our data demonstrate that brown fat Dnmt3b is a key regulator of brown fat development, energy metabolism and obesity in female mice.
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Project description:Brown adipose tissue (BAT), an organ that burns energy through uncoupling thermogenesis, is a promising therapeutic target for obesity. However, there are still no safe anti-obesity drugs that target BAT in the market. In the current study, we performed large scale screening of 636 compounds which were approved by Food and Drug Administration (FDA) to find drugs that could significantly increase uncoupling protein 1 (UCP1) mRNA expression by real-time PCR. Among those UCP1 activators, most of them were antibiotics or carcinogenic compounds. We paid particular attention to fluvastatin sodium (FS), because as an inhibitor of the cellular hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase, FS has already been approved for treatment of hypercholesteremia. We found that in the cellular levels, FS treatment significantly increased UCP1 expression and BAT activity in human brown adipocytes. Consistently, the expression of oxidative phosphorylation-related genes was significantly increased upon FS treatment without differences in adipogenic gene expression. Furthermore, FS treatment resisted to high-fat diet (HFD)-induced body weight gain by activating BAT in the mice model. In addition, administration of FS significantly increased energy expenditure, improved glucose homeostasis and ameliorated hepatic steatosis. Furthermore, we reveal that FS induced browning in subcutaneous white adipose tissue (sWAT) known to have a beneficial effect on energy metabolism. Taken together, our results clearly demonstrate that as an effective BAT activator, FS may have great potential for treatment of obesity and related metabolic disorders.
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Project description:Obesity induces accumulation of adipose tissue macrophages (ATMs) and ATM-driven inflammatory responses that promote the development of glucose and lipid metabolism disorders. ClC-3 chloride channel/antiporter, encoded by the Clcn3, is critical for some basic cellular functions. Our previous work has shown significant alleviation of type 2 diabetes in Clcn3 knockout (Clcn3-/-) mice. In the present study we investigated the role of Clcn3 in high-fat diet (HFD)-induced obesity and ATM inflammation. To establish the mouse obesity model, both Clcn3-/- mice and wild-type mice were fed a HFD for 4 or 16 weeks. The metabolic parameters were assessed and the abdominal total adipose tissue was scanned using computed tomography. Their epididymal fat pad tissue and adipose tissue stromal vascular fraction (SVF) cells were isolated for analyses. We found that the HFD-fed Clcn3-/- mice displayed a significant decrease in obesity-induced body weight gain and abdominal visceral fat accumulation as well as an improvement of glucose and lipid metabolism as compared with HFD-fed wild-type mice. Furthermore, the Clcn3 deficiency significantly attenuated HFD-induced ATM accumulation, HFD-increased F4/80+ CD11c+ CD206- SVF cells as well as HFD-activated TLR-4/NF-κB signaling in epididymal fat tissue. In cultured human THP-1 macrophages, adenovirus-mediated transfer of Clcn3 specific shRNA inhibited, whereas adenovirus-mediated cDNA overexpression of Clcn3 enhanced lipopolysaccharide-induced activation of NF-κB and TLR-4. These results demonstrate a novel role for Clcn3 in HFD-induced obesity and ATM inflammation.
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Project description:Postmenopausal women have a higher susceptibility to obesity and chronic disease. Piceatannol (PIC), a natural analog of resveratrol, was reported to inhibit adipogenesis and to have an antiobesity effect. In this study, PIC's effect on postmenopausal obesity and the mechanism of its action were investigated. C57BL/6J female mice were divided into four groups and half of them were ovariectomized (OVX). Both OVX and sham-operated mice were fed a high-fat diet (HFD) with and without the addition of 0.25% of PIC for 12 weeks. The abdominal visceral fat volume was higher in the OVX mice than the sham-operated mice, and PIC significantly decreased the fat volume only in the OVX mice. Unexpectedly, expression levels of adipogenesis-related proteins in white adipose tissue (WAT) were suppressed in the OVX mice, and PIC did not affect lipogenesis in either the OVX or sham-operated mice. Regarding the expression of proteins associated with lipolysis, PIC activated the phosphorylation of hormone-sensitive lipase much more in the OVX mice, but it did not affect the expression of adipose triglyceride lipase. PIC also tended to induce the expression of uncoupled protein 1 in brown adipose tissue (BAT). These results suggest that by promoting lipolysis in WAT and deconjugation in BAT, PIC is a potential agent to inhibit fat accumulation caused by menopause.
| S-EPMC10056039 | biostudies-literature
Project description:Cytochrome P450 1B1 (CYP1B1) expression increases in multi-potential mesenchymal stromal cells C3H10T1/2 during adipogenesis, which parallel with PPAR?, a critical transcriptional factor in adipogenic process. To assess the role of CYP1B1 in fatty acid metabolism, adult C57BL/6J wild-type and CYP1B1 deficiency mice were fed with high fat diets (HFD) for 6 weeks. CYP1B1 deficiency attenuated HFD-induced obesity when compared with their wild type counterparts, and improve glucose tolerance. The reduction in body weight gain and white adipose tissue in CYP1B1 deficient mice exhibited coordinate decreases in fatty acid synthesis (PPAR?, CD36, FAS, SCD-1) and increases in fatty acid oxidation (UCP-2, CPT-1a) when compared with wild type ones. Lower hepatocyte TG contents were consistent with hepatic Oil-Red-O staining in the CYP1B1 deficiency mice. AMPK, a nutrient sensors for energy homeostasis, was activated in both fat pad and liver by CYP1B1 deficiency. However, in vitro system, knock down CYP1B1 in C3H10T1/2 cells does not abolish adipogenesis induced by adipogenic agents IDM (Insulin, Dexamethasone, Methylisobutylxanthine). Our in vivo and in vitro findings of CYP1B1 deficiency in fat metabolism suggest a complex regulation network between CYP1B1 and energy homeostasis.
| S-EPMC4455350 | biostudies-literature
Project description:Although macroautophagy/autophagy deficiency causes degenerative diseases, the deletion of essential autophagy genes in adipocytes paradoxically reduces body weight. Brown adipose tissue (BAT) plays an important role in body weight regulation and metabolic control. However, the key cellular mechanisms that maintain BAT function remain poorly understood. in this study, we showed that global or brown adipocyte-specific deletion of pink1, a Parkinson disease-related gene involved in selective mitochondrial autophagy (mitophagy), induced BAT dysfunction, and obesity-prone type in mice. Defective mitochondrial function is among the upstream signals that activate the NLRP3 inflammasome. NLRP3 was induced in brown adipocyte precursors (BAPs) from pink1 knockout (KO) mice. Unexpectedly, NLRP3 induction did not induce canonical inflammasome activity. Instead, NLRP3 induction led to the differentiation of pink1 KO BAPs into white-like adipocytes by increasing the expression of white adipocyte-specific genes and repressing the expression of brown adipocyte-specific genes. nlrp3 deletion in pink1 knockout mice reversed BAT dysfunction. Conversely, adipose tissue-specific atg7 KO mice showed significantly lower expression of Nlrp3 in their BAT. Overall, our data suggest that the role of mitophagy is different from general autophagy in regulating adipose tissue and whole-body energy metabolism. Our results uncovered a new mitochondria-NLRP3 pathway that induces BAT dysfunction. The ability of the nlrp3 knockouts to rescue BAT dysfunction suggests the transcriptional function of NLRP3 as an unexpected, but a quite specific therapeutic target for obesity-related metabolic diseases.Abbreviations: ACTB: actin, beta; BAPs: brown adipocyte precursors; BAT: brown adipose tissue; BMDMs: bone marrow-derived macrophages; CASP1: caspase 1; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; ChIP: chromatin immunoprecipitation; EE: energy expenditure; HFD: high-fat diet; IL1B: interleukin 1 beta; ITT: insulin tolerance test; KO: knockout; LPS: lipopolysaccharide; NLRP3: NLR family, pyrin domain containing 3; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RD: regular diet; ROS: reactive oxygen species; RT: room temperature; UCP1: uncoupling protein 1 (mitochondrial, proton carrier); WT: wild-type.
| S-EPMC8143238 | biostudies-literature
Project description:Obesity is caused by a long-term imbalance between energy intake and consumption and is regulated by multiple signals. This study investigated the effect of signaling scaffolding protein Gab2 on obesity and its relevant regulation mechanism. Gab2 knockout (KO) and wild-type (WT) mice were fed with a standard diet (SD) or high-fat diet (HFD) for 12 weeks. The results showed that the a high-fat diet-induced Gab2 expression in adipose tissues, but deletion of Gab2 attenuated weight gain and improved glucose tolerance in mice fed with a high-fat diet. White adipose tissue and systemic inflammations were reduced in HFD-fed Gab2 deficiency mice. Gab2 deficiency increased the expression of Ucp1 and other thermogenic genes in brown adipose tissue. Furthermore, the regulation of Gab2 on the mature differentiation and function of adipocytes was investigated in vitro using primary or immortalized brown preadipocytes. The expression of brown fat-selective genes was found to be elevated in differentiated adipocytes without Gab2. The mechanism of Gab2 regulating Ucp1 expression in brown adipocytes involved with its downstream PI3K (p85)-Akt-FoxO1 signaling pathway. Our research suggests that deletion of Gab2 suppresses diet-induced obesity by multiple pathways and Gab2 may be a novel therapeutic target for the treatment of obesity and associated complications.
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Project description:PurposeTo investigate the effect of cocoa powder supplementation on obesity-related inflammation in high fat (HF)-fed obese mice.MethodsMale C57BL/6J (n = 126) were fed with either low-fat (LF, 10 % kcal from fat) or HF (60 % kcal from fat) diet for 18 weeks. After 8 weeks, mice from HF group were randomized to HF diet or HF diet supplemented with 8 % cocoa powder (HF-HFC group) for 10 weeks. Blood and tissue samples were collected for biochemical analyses.ResultsCocoa powder supplementation significantly reduced the rate of body weight gain (15.8 %) and increased fecal lipid content (55.2 %) compared to HF-fed control mice. Further, cocoa supplementation attenuated insulin resistance, as indicated by improved HOMA-IR, and reduced the severity of obesity-related fatty liver disease (decreased plasma alanine aminotransferase and liver triglyceride) compared to HF group. Cocoa supplementation also significantly decreased plasma levels of the pro-inflammatory mediators interleukin-6 (IL-6, 30.4 %), monocyte chemoattractant protein-1 (MCP-1, 25.2 %), and increased adiponectin (33.7 %) compared to HF-fed mice. Expression of pro-inflammatory genes (Il6, Il12b, Nos2, and Emr1) in the stromal vascular fraction (SVF) of the epididymal white adipose tissue (WAT) was significantly reduced (37-56 %) in the cocoa-supplemented mice.ConclusionsDietary supplementation with cocoa ameliorates obesity-related inflammation, insulin resistance, and fatty liver disease in HF-fed obese mice, principally through the down-regulation of pro-inflammatory gene expression in WAT. These effects appear to be mediated in part by a modulation of dietary fat absorption and inhibition of macrophage infiltration in WAT.
| S-EPMC3818345 | biostudies-literature
Project description:AIMS/HYPOTHESIS:Hypomagnesaemia (blood Mg2+ <0.7 mmol/l) is a common phenomenon in individuals with type 2 diabetes. However, it remains unknown how a low blood Mg2+ concentration affects lipid and energy metabolism. Therefore, the importance of Mg2+ in obesity and type 2 diabetes has been largely neglected to date. This study aims to determine the effects of hypomagnesaemia on energy homeostasis and lipid metabolism. METHODS:Mice (n?=?12/group) were fed either a low-fat diet (LFD) or a high-fat diet (HFD) (10% or 60% of total energy) in combination with a normal- or low-Mg2+ content (0.21% or 0.03% wt/wt) for 17 weeks. Metabolic cages were used to investigate food intake, energy expenditure and respiration. Blood and tissues were taken to study metabolic parameters and mRNA expression profiles, respectively. RESULTS:We show that low dietary Mg2+ intake ameliorates HFD-induced obesity in mice (47.00?±?1.53 g vs 38.62?±?1.51 g in mice given a normal Mg2+-HFD and low Mg2+-HFD, respectively, p?<?0.05). Consequently, fasting serum glucose levels decreased and insulin sensitivity improved in low Mg2+-HFD-fed mice. Moreover, HFD-induced liver steatosis was absent in the low Mg2+ group. In hypomagnesaemic HFD-fed mice, mRNA expression of key lipolysis genes was increased in epididymal white adipose tissue (eWAT), corresponding to reduced lipid storage and high blood lipid levels. Low Mg2+-HFD-fed mice had increased brown adipose tissue (BAT) Ucp1 mRNA expression and a higher body temperature. No difference was observed in energy expenditure between the two HFD groups. CONCLUSIONS/INTERPRETATION:Mg2+-deficiency abrogates HFD-induced obesity in mice through enhanced eWAT lipolysis and BAT activity.
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Project description:Pharmacological treatment of recombinant growth differentiation factor 15 (GDF15) proteins reduces body weight in obese rodents and primates. Paradoxically, circulating GDF15 levels are increased in obesity. To investigate the role of endogenous GDF15 in obesity development, we put GDF15 knockout mice and wildtype controls on high fat diet for the mice to develop diet-induced obesity. Compared to wildtype animals, GDF15 knockout mice were more prone to high fat diet-induced obesity. Male knockout mice showed worse glucose tolerance, lower locomotor activity and lower metabolic rate than wildtype mice. Additionally, GDF15 deficiency increased occurrences of high fat diet-induced skin lesions. Our data suggests that endogenous GDF15 has a protective role in obesity development and lack of GDF15 aggravates the progression of obesity and associated pathological conditions. Elevated GDF15 levels in obesity may have resulted from a response to overcome GDF15 resistance.
| S-EPMC6072047 | biostudies-literature