Succinate Modulation as a Novel Mechanism Underlying the Effects of Intermittent Fasting on Brain Function and Metabolism in Diet-Induced Obesity
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE298120 | GEO | 2026/04/08
REPOSITORIES: GEO
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Project description:Activated brown adipose tissue contributes to control of energy and glucose homeostasis in rodents and humans. Defining cell-autonomous processes underlying BAT differentiation and activation may thus reveal novel therapeutic targets for obesity and type 2 diabetes mellitus intervention. Here we show that ageing- and obesity-associated demises in BAT function coincide with down-regulation of mature microRNAs in BAT in the presence of reduced expression of the critical microRNA processing enzyme Dicer1. To mimic this partial down-regulation of microRNA processing in obesity and ageing, we inactivated one allele of Dicer1 selectively in BAT of mice. BAT- restricted heterozygosity of Dicer1 caused glucose intolerance in lean mice and aggravated diet-induced-obesity (DIO)-evoked deterioration of glucose homeostasis. Using combinatorial analyses of altered microRNA-expression in BAT during in vitro preadipocyte commitment and mouse models of progeria, longevity and DIO, we identified 23 microRNAs dysregulated among these conditions. Of these, we identified miR-328 as a novel regulator of BAT differentiation. miR-328 over-expression promotes BAT-differentiation and impairs muscle progenitor commitment, while reducing miR-328 expression blocks BAT specification. We validated the ß-Secretase Bace1 as a target of miR-328, which is consequently over-expressed in BAT of obese and premature ageing mice. Reducing Bace1 expression enhances brown adipocyte, while impairing myogenic differentiation in vitro. In vivo small-molecule Bace1 inhibition in obese mice delayed DIO-induced weight gain, ameliorated obesity-associated deterioration of glucose metabolism and improved insulin sensitivity. Collectively, these experiments reveal reduced Dicer1-miR-328-Bace1 axis in presence of generalized impairment of microRNA processing in ageing and obesity as a novel determinant of ageing- and obesity-associated decline in BAT function. This may define in vivo Bace1-inhibition as an innovative therapeutic approach to not only target age-related neurodegenerative diseases but at the same time improving age-related impairment of BAT-function and metabolism. C57BL/6 mice ( 4 weeks of age) were treated with a calory-rich, high-sugar high-fat diet (HFD) for a course of 4 weeks. Then groups were stratified and one group continued to receive HFD (BAT13-15) or HFD supplemented with an experimental small-molecule Bace 1 inhibitor (BAT17, 33, 35).
2015-06-17 | E-GEOD-69913 | biostudies-arrayexpress
Project description:Background: Obesity driven by high-fat diet (HFD) is a global public health concern, and Pu-erh tea extract (PTE) exhibits anti-obesity potential, but its regulatory mechanism on brown adipose tissue (BAT) metabolism remains unclear. Transcriptomic analysis of BAT is critical to reveal PTE-mediated metabolic remodeling. Methods: C57BL/6J mice were divided into HFD (high-fat diet) and HFD+PTE groups. BAT samples were collected after 16-week intervention for RNA sequencing. Results: Transcriptomic data showed 623 differentially expressed genes (DEGs) in HFD+PTE vs HFD groups, mainly enriched in cAMP/Calcium signaling, Biosynthesis of unsaturated fatty acids, and Glycerolipid metabolism pathways. Value: This dataset provides transcriptomic evidence for PTE regulating BAT function, complementing our previously deposited gut microbiota 16S rRNA data, and facilitating research on natural product-mediated metabolic regulation.
2025-12-12 | GSE312855 | GEO
Project description:Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole-body energy expenditure, counteracts obesity, and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs). We show that succinate transport is strongly dependent on the proportion of it present in the monocarboxylate form. MCTs facilitate monocarboxylate succinate uptake, which is promoted by alkalinization of the cytosol driven by adrenoreceptor stimulation. In brown adipocytes, we show that MCT1 primarily facilitates succinate import. In mice, we show that both acute pharmacological inhibition of MCT1 and congenital depletion of MCT1, decrease succinate uptake into BAT and consequent catabolism. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.
2024-01-10 | PXD048056 | Pride
Project description:Obesity is associated with chronic diseases such as atherosclerosis and type 2 diabetes. In obesity, brown adipose tissue (BAT) activity declines, and lipid accumulation impairs its function. Dihydromyricetin (DHM) exhibits multiple biological functions, including inhibiting adipogenesis, promoting lipolysis, suppressing mitochondrial autophagy, and exerting anti-inflammatory and antioxidant effects, collectively demonstrating significant potential in obesity prevention and treatment. However, research on DHM's mechanisms in the BAT of obese mice remains limited. In this study, we performed single-nucleus RNA sequencing (snRNA-seq) to systematically characterize obesity-induced BAT dysfunction and DHM's effects at single-cell resolution in high-fat diet (HFD)-fed C57BL/6J mice. The results demonstrated that DHM ameliorated HFD-induced brown adipocyte dysfunction by modulating energy balance in Ad3 and Ad5 adipocyte subpopulations, promoting lipolysis, suppressing pro-inflammatory factor expression, inhibiting extracellular matrix remodeling, and regulating adipocyte-perivascular cell interactions. These findings provide insights into DHM's role in preventing BAT dysfunction and support its clinical application for obesity.
2025-10-02 | GSE296575 | GEO
Project description:Obesity induces macrophages to drive inflammation in adipose tissue, a crucial step towards the development of type 2 diabetes. The tricarboxylic acid (TCA) cycle intermediate succinate is released from cells under metabolic stress and has recently emerged as a metabolic signal induced by proinflammatory stimuli. We therefore investigated whether succinate receptor 1 (SUCNR1) could play a role in the development of adipose tissue inflammation and type 2 diabetes. Succinate levels were determined in human plasma samples from individuals with type 2 diabetes and non-diabetic participants. Succinate release from adipose tissue explants was studied. Sucnr1 -/- and wild-type (WT) littermate mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 16 weeks. Serum metabolic variables, adipose tissue inflammation, macrophage migration and glucose tolerance were determined. We show that hypoxia and hyperglycaemia independently drive the release of succinate from mouse adipose tissue (17-fold and up to 18-fold, respectively) and that plasma levels of succinate were higher in participants with type 2 diabetes compared with non-diabetic individuals (+53%; p < 0.01). Sucnr1 -/- mice had significantly reduced numbers of macrophages (0.56 ± 0.07 vs 0.92 ± 0.15 F4/80 cells/adipocytes, p < 0.05) and crown-like structures (0.06 ± 0.02 vs 0.14 ± 0.02, CLS/adipocytes p < 0.01) in adipose tissue and significantly improved glucose tolerance (p < 0.001) compared with WT mice fed an HFD, despite similarly increased body weights. Consistently, macrophages from Sucnr1 -/- mice showed reduced chemotaxis towards medium collected from apoptotic and hypoxic adipocytes (-59%; p < 0.05). Our results reveal that activation of SUCNR1 in macrophages is important for both infiltration and inflammation of adipose tissue in obesity, and suggest that SUCNR1 is a promising therapeutic target in obesity-induced type 2 diabetes.
2017-04-07 | GSE64104 | GEO
Project description:The long noncoding RNA (lncRNA) lnc-Megacluster (lncMGC) is implicated in diabetic kidney disease and pancreatic islet dysfunction. However, its role in obesity and insulin resistance (IR) is unknown. Herein, we investigated the regulatory role of lncMGC in obesity and adipose dysfunction using lncMGC knockout (KO) mice, and further determined the translational potential of lncMGC-based therapeutics for obesity using GapmeR antisense oligonucleotides in wild-type and partially humanized-lncMGC mice. We found lncMGC is upregulated in perigonadal white adipose (gWAT) and brown adipose tissues (BAT) from high-fat diet (HFD)-induced obese mice along with increased endoplasmic reticulum stress signaling. Inhibition of lncMGC in mice via genetic ablation or GapmeRs targeting mouse or human lncMGC displayed protective effects against HFD-induced IR, weight gain, and associated adipose dysfunction. In parallel, key lncMGC targets involved in gWAT and BAT functions were altered. The metabolic beneficial effects in gWAT were accompanied by improved angiogenesis, reduced adipocyte hypertrophy, and inflammation. Notably, lowering lncMGC levels in HFD-fed lncMGC KO or via GapmeR treatment enhanced BAT functional markers, mitochondrial thermogenic program/structure, and mitophagy markers. Collectively, these new findings underscore the pathogenic role of lncMGC in adipose dysfunction and the therapeutic potential of targeting key lncRNAs for obesity and associated metabolic dysfunction.
2026-01-21 | GSE293681 | GEO
Project description:The increasing incidence of obesity poses great challenges and demands for developing effective therapeutic approaches. We aimed to reveal the anti-obesity effects of tetrahydroberberrubine (THBru), a derivative of berberine (BBR) and elucidate its underlying mechanism. The anti-obesity effects of THBru and BBR were assessed and compared using an obese mouse model induced by high fat diet (HFD). THBru was found to markedly ameliorated obesity, indicated by reduced body weight, decreased Lee’s index, lowered epididymal white adipose tissue (WAT) and brown adipose tissue (BAT) fat mass as well as improved dyslipidemia. At the same dose, THBru produced greater anti-obesity effects than BBR. RNA-sequencing and gene set enrichment analysis indicated THBru activated thermogenesis, which was further confirmed in WAT, BAT, and 3T3-L1 cells. Bioinformatics analysis of RNA-sequencing data revealed the candidate gene Pgc1α, a key regulator involved in thermogenesis. Moreover, THBru was demonstrated to elevate the expression of PGC1α by stabilizing its mRNA in WAT, BAT and 3T3-L1 cells. Furthermore, PGC1α knockdown blocked the pro-thermogenic and anti-obesity action of THBru both in vivo and in vitro. This study indicated THBru exerted anti-obesity effects by activating PGC1α-mediated thermogenesis and outlined its potential preventive and therapeutic implications for obesity and related diseases.
2025-05-01 | GSE264072 | GEO
Project description:Diet-induced obesity (DIO) induces growth differentiation factor 15 (GDF15) in various tissues, leading to increased GDF15 serum levels. The liver is the primary source of circulating GDF15 during DIO, but other tissues are also required. We investigated whether brown adipose tissue (BAT) contributes to GDF15 circulating levels and whether Gdf15 induction in BAT regulates systemic metabolism during DIO. We generated mice with selective Gdf15 deletion in thermogenic adipocytes (KO) and subjected them to 12 weeks of high-fat diet (HFD) feeding. Although in ad-libitum fed conditions GDF15 serum levels were unchanged between genotypes regardless of sex, female KO mice demonstrated reduced food intake, increased mitochondrial fatty acid oxidation in BAT, and were resistant to DIO, which was prevented by ovariectomy. Conversely, male KO mice demonstrated increased food intake, reduced mitochondrial respiratory capacity, and increased fibro-inflammation in BAT, resulting in increased body weight and fat mass accrual. Together, our data show that Gdf15 expression in BAT is required to regulate energy metabolism in mice in a sex-dependent manner.
2025-12-31 | GSE296580 | GEO
Project description:Thoracic perivascular adipose tissue (PVAT) is a unique adipose depot that likely influences vascular function and susceptibility to pathogenesis in obesity and metabolic syndrome. Surprisingly, PVAT has been reported to share characteristics of both brown and white adipose, but a detailed direct comparison to interscapular brown adipose tissue (BAT) has not been performed. Here we show by full genome DNA microarray analysis that global gene expression profiles of PVAT are virtually identical to BAT, with equally high expression of Ucp-1, Cidea and other genes known to be uniquely or very highly expressed in BAT. PVAT and BAT also displayed nearly identical phenotypes upon immunohistochemical analysis, and electron microscopy confirmed that PVAT contained multilocular lipid droplets and abundant mitochondria. Compared to white adipose tissue (WAT), PVAT and BAT from C57BL/6 mice fed a high fat diet for 13 weeks had markedly lower expression of immune cell-enriched mRNAs, suggesting resistance to obesity-induced inflammation. Indeed, staining of BAT and PVAT for macrophage markers (F4/80, CD68) in obese mice showed virtually no macrophage infiltration, and FACS analysis of BAT confirmed the presence of very few CD11b+/CD11c+ macrophages in BAT (1.0%) in comparison to WAT (31%). In summary, murine PVAT from the thoracic aorta is virtually identical to interscapular BAT, is resistant to diet-induced macrophage infiltration, and thus may play an important role in protecting the vascular bed from thermal and inflammatory stress. 8-week-old male C57BL6/J mice were fed a normal (ND) or high fat diet (HFD) (Research Diets 12451, 45 kcal% fat) for 13 weeks. Mice were then euthanized and four different adipose depots were harvested for RNA analysis: perivascular fat from the lesser curvature of the aortic arch (PVAT), interscapular brown adipose (BAT), inguinal adipose tissue (SAT), and epididymal adipose tissue (VAT). 250 ng total RNA pooled from two mice was used for cDNA synthesis; 3 biological replicates per tissue and diet were performed for a total of 24 hybridizations.
2011-08-22 | E-GEOD-28440 | biostudies-arrayexpress
Project description:Obesity is a growing global concern in adults and youth along with a parallel rise in associated complications, including cognitive impairment. Obesity induces brain inflammation and activates microglia, which contribute to cognitive impairment by aberrantly phagocytosing synaptic spines. Local and systemic signals, such as inflammatory cytokines and metabolites likely participate in obesity-induced microglial activation. However, the precise mechanisms mediating microglial activation during obesity remain incompletely understood. Herein, we leveraged our mouse model of high-fat diet (HFD)-induced obesity, which mirrors human obesity, and develops hippocampal-dependent cognitive impairment. We assessed hippocampal microglial activation by morphological and single-cell transcriptomic analysis to evaluate this heterogeneous, functionally diverse, and dynamic class of cells over time after 1 and 3 months of HFD. HFD altered cell-to-cell communication, particularly immune modulation and cellular adhesion signaling, and induced a differential gene expression signature of protein processing in the endoplasmic reticulum in a time-dependent manner.
2023-02-17 | GSE217464 | GEO