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At least 19 recordsLinked to original sources
PubMed2024

Dissecting the anti-obesity components of ginseng: How ginseng polysaccharides and ginsenosides target gut microbiota to suppress high-fat diet-induced obesity.

INTRODUCTION: Ginseng demonstrates therapeutic potential in treating obesity, with both experimental and clinical studies suggesting its anti-obesity effects are mediated by gut microbiota. Nonetheless, the specific chemical components responsible for this effect remain largely unidentified. OBJECTIVES: This study aims to investigate the anti-obesity effects and mechanisms of ginseng polysaccharides (GP) and ginsenosides (GS), the primary chemical components of ginseng, with a focus on their impact on gut microbiota. METHODS: The impact of GP and GS on high-fat diet (HFD)-induced obesity was assessed using a mouse model. Molecular mechanisms were explored through a combination of chemical analysis, metagenomics, RT-qPCR, ELISA, and biochemical assays. RESULTS: GP or GS administration effectively prevented adiposity in HFD-fed mice, and both effects were mediated by gut microbiota. Chemical analysis revealed diverse glycosyl groups in GP and GS. Metagenomics data suggested that GP-enriched species, e.g., Bacteroides stercorirosoris and Clostridiales bacterium encoded carbohydrate-active enzymes GH35, GH43 and PL9_1, while GS-enriched Sulfurospirillum halorespirans encoded GH16_5. These enzymes facilitated the utilization of glycosyl groups in GP and GS, selectively stimulating bacterial growth and reshaping the gut microbiota. Furthermore, bacterial species enriched by GP or GS encoded specific functional genes involved in short-chain fatty acid (SCFA) synthesis (K00625 and K00925 for GP; K18118, K00100, and K18122 for GS) and intestinal gluconeogenesis (IGN) (K01678, K00024, and K01596 for GP; K18118 and K00278 for GS). Consequently, the SCFA-GLP-1/PYY signaling and IGN were activated by both GP and GS to ameliorate obesity phenotypes. CONCLUSION: GP and GS, containing diverse glycosyl groups, selectively stimulate specific gut bacteria, triggering mechanisms involved in SCFA-GLP-1/PYY signaling and IGN activation to reduce adiposity in HFD-fed mice. The study enhances understanding of the chemical components crucial for the gut microbiota-mediated anti-obesity effect of ginseng. The mechanistic understanding provides valuable insights for developing ginseng-based drugs or health products to combat obesity.

Gastrointestinal Microbiome↗
PubMed2026

Opposite metabolic and gut responses to oral glutamine in male and female mice with diet-induced obesity.

Obesity is often associated with sex-dependent metabolic complications, to which altered intestinal barrier function and gut microbiota contribute. Glutamine supplementation has previously shown beneficial effects on gut barrier function and glycemic control. We thus aimed to characterize, in male and female mice, the effects of oral glutamine supplementation during high-fat-diet-induced obesity. Male and female C57BL/6 mice received a standard (SD) or high-fat diet (HFD; 60 % kcal from fat) for 14 weeks (W14). From W12 onward, mice received glutamine in drinking water (2 g/kg/day) or no supplementation. Body composition, glucose tolerance, insulin sensitivity, intestinal permeability, colonic inflammatory response, cecal microbiota and inflammatory/endocrine adipose response were assessed. In both male and female mice, glutamine supplementation failed to improve body weight and body composition. However, glutamine reduced glucose intolerance in HFD-fed males (AUC reduced by 14.57 %) that was associated with a partial restoration of plasma resistin and insulin and a trend toward limiting adipose inflammatory response. In males, glutamine did not affect gut microbiota composition and colonic response. Conversely, in HFD-fed females, glutamine supplementation led to gut microbiota changes (increase in Bacteroidota and Pseudomonadota phyla; increase in Muribaculaceae and Tannerellaceae families), increased colonic inflammatory markers (Il1b, Tlr4, Myd88, Irf3), increased inflammatory response in subcutaneous adipose tissue and increased HOMA-IR. Finally, HFD-fed mice exhibited sex-specific responses to glutamine supplementation with protective effects in males and harmful effects in females that need to be further deeply explored.

Animals↗
PubMed2025

Adipocyte-specific IGF1R knockout activates the β-catenin/apelin axis to combat diet-induced obesity in male mice.

AIMS: Obesity, driven by complex genetic and environmental interactions, remains a global health crisis with limited therapeutic options. The insulin-like growth factor 1 receptor (IGF1R) plays dual roles in metabolism and growth, but its tissue-specific functions in adipose biology are controversial. This study investigates how adipose-specific IGF1R knockout impacts systemic metabolism under high-fat diet (HFD) stress and explores the underlying mechanisms. METHODS: Adipose-specific IGF1R knockout mice (AdIGF1RKO) were generated by crossing Igf1rfl/fl mice with Adipoq-Cre transgenics. Mice were fed a normal chow diet (NCD) or HFD for 20 weeks. Metabolic phenotyping included glucose/insulin tolerance tests, body composition analysis and serum profiling. RNA-seq, Western blot and quantitative real-time reverse transcriptase PCR were used to identify molecular pathways. In vitro studies with stromal vascular fraction (SVF) cells validated β-catenin/apelin interactions. RESULTS: AdIGF1RKO male mice exhibited reduced adipose mass under NCD and resisted HFD-induced obesity, showing attenuated hepatic lipid deposition and improved glucose metabolism. Mechanistically, IGF1R knockout enhanced INSR and Akt phosphorylation, driving GSK3β-β-catenin activation and apelin upregulation. Apelin activated AMPK, suppressing lipogenesis and enhancing fatty acid oxidation. Notably, β-catenin's role shifted from inhibiting adipogenesis in precursors to promoting metabolic adaptation in mature adipocytes. CONCLUSION: We unveil a β-catenin/apelin-driven endocrine axis that reprograms energy metabolism under obesogenic stress. Therapeutically, targeting adipose IGF1R or apelin signalling could combat obesity while avoiding systemic toxicity. Limitations include unresolved β-catenin/Apln transcriptional mechanisms, APJ function and tissue-specific AMPK effects. Our findings redefine IGF1R's metabolic role and propose novel strategies for obesity-related disorders.

Animals↗
PubMed1977

Comparison of metabolic alterations in hypothalamic and high fat diet-induced obesity.

The heterogeneous nature of the experimental obesities induced by ventromedial hypothalamic (VMH) lesion and high fat diet (HFD) have been demonstrated by comparing VMH-lesioned and sham-operated rats fed a HFD or low fat diet (LFD). VMH rats had increased fat mass serum insulin and serum triglycerides but lower serum glucagon and smaller salivary glands than sham-operated animals. The body weight of HFD obese rats was intermediate between VMH and sham-operated animals on the LDF. Liver and fat pad weights showed effects of lesions and diet. Diet did not affect plasma glucagon or insulin. Pair-feeding VMH rats with sham-operated rats prevented weight gain but did not prevent the increase in insulin and fall in glucagon. Studies of insulin secretion from isolated perifused islets showed that basal and both phases of stimulated secretion were significantly increased in VMH groups. The changes in plasma insulin, plasma glucagon, and salivary gland weight in VMH groups are interpreted as showing decreased activity of the sympathetic nervous system following VMH lesions.

Animals↗
PubMed2026

Food-derived extracellular vesicles as delivery platforms for medicine-food homology components in metabolic syndrome.

Diet-induced obesity and associated metabolic syndromes have become major global public health challenge, highlighting the urgent need for safe and effective strategies. Recently, food-derived extracellular vesicles (FDEVs) have garnered increasing attention as natural nanocarriers due to their excellent biocompatibility and specific targeted delivery capabilities. FDEVs can efficiently deliver medicine-food homology components (MFHCs) to precisely regulate lipid metabolism, inflammatory responses, and insulin sensitivity, thereby improving obesity and its metabolic abnormalities. This systematic review summarizes recent advances in the use of FDEVs as delivery vehicles for MFHCs to suppress diet-induced obesity and metabolic syndrome, with a particular focus on the underlying molecular mechanisms, including signaling pathway regulation and cellular metabolic remodeling. In addition, the clinical translational potential and industrial application prospects of FDEVs are evaluated, and key challenges related to preparation techniques, safety assessment, and large-scale production are discussed. By integrating current evidence, this review aims to provide theoretical framework and future perspectives for the development of FDEVs as a novel targeted delivery platform and treatment of metabolic diseases.

Extracellular Vesicles↗
PubMed2026

Linking visceral fat accumulation to gut microbiota: key bacterial taxa and their roles in the glycogen synthesis pathway.

Obesity, marked by visceral fat accumulation, has a complex relationship with the gut microbiome that impacts body weight and fat accumulation. However, previous studies did not account for fat distribution, reflecting only overall fat mass, leaving specifics of this relationship partially understood. Here we analyzed the mechanistic links between visceral fat and the microbiome in a large cohort of healthy Koreans. Using permutational multivariate analysis of variance and prediction modeling, we examined associations between microbial profiles and metabolic variables including insulin, triglycerides, waist circumference and visceral fat. The strongest correlations were noted with specific enterotypes. Shotgun sequencing revealed that visceral fat is linked to the glycogen synthesis pathway influenced by Dorea longicatena and Bifidobacterium adolescentis. This suggests that these specific microbial signatures and their associated functional potential play a role in visceral fat-related obesity. To validate these findings, we conducted an in vivo study using diet-induced obesity mouse model. Oral administration of D. longicatena or B. adolescentis significantly promoted body weight gain and fat mass expansion and induced hepatic lipogenic gene upregulation. The prevalence of these strains in Korean and American populations highlights their global relevance, contributing to the development of personalized treatments and advanced health strategies.

Journal Article↗
PubMed2026

Celery seed extract attenuates sarcopenic obesity and age-related sarcopenia by reducing intramuscular lipid accumulation in mice.

BACKGROUND & AIMS: Sarcopenia is characterized by progressive loss of skeletal muscle mass and function and is increasingly recognized to be influenced by metabolic disturbances associated with aging and obesity. Intramuscular lipid accumulation has emerged as a key pathological feature linking metabolic dysfunction to skeletal muscle deterioration. Celery seed extract (CSE) possesses anti-obesity, anti-inflammatory, and antioxidant properties; however, its potential role in skeletal muscle metabolism has not been well investigated. This study aimed to determine whether CSE attenuates skeletal muscle deterioration associated with obesity and aging through modulation of intramuscular lipid accumulation and related metabolic pathways. METHODS: Diet-induced obese mice and naturally aged mice were used to evaluate the effects of CSE supplementation. Skeletal muscle mass, grip strength, muscle morphology, intramuscular lipid content, mitochondrial metabolic signaling, inflammatory responses, and muscle protein turnover pathways were assessed using biochemical, molecular, and histological analyses. RESULTS: CSE supplementation significantly improved skeletal muscle mass, grip strength, and muscle fiber cross-sectional area in both obese and aged mice. These improvements were accompanied by reduced intramuscular triglyceride and cholesterol accumulation. Mechanistically, CSE improved mitochondrial metabolic signaling by activating the AMPK-PGC-1α pathway and increasing mitochondrial oxidative phosphorylation proteins. In addition, CSE suppressed inflammatory signaling pathways, including MAPK activation and NLRP3 inflammasome signaling, and improved muscle proteostasis by enhancing myogenic regulators while reducing the expression of proteolytic factors such as MuRF1, Atrogin-1, and myostatin. Correlation analyses further indicated that intramuscular lipid accumulation was closely associated with mitochondrial dysfunction, inflammatory activation, and muscle atrophy. CONCLUSIONS: These findings demonstrate that CSE alleviates skeletal muscle deterioration in both obesity- and aging-associated sarcopenia by reducing intramuscular lipid accumulation and improving mitochondrial metabolism, inflammatory responses, and muscle protein turnover. Targeting intramuscular lipid accumulation may therefore represent a promising nutritional strategy for preventing sarcopenia associated with metabolic and aging-related stress.

AMPK–PGC-1α↗
PubMed2026

Metabolic and endocrine modulation of the gut-adipose tissue axis via pro-, pre-, and postbiotics in overweight dogs: A systematic review.

Canine obesity is a complex metabolic disorder driven by luminal dysbiosis, impaired gut barrier function, and metaflammation. Following PRISMA 2020 guidelines, this systematic review evaluated the efficacy of pro-, pre-, and postbiotics in modulating the gut-adipose tissue axis in overweight dogs (BCS ≥ 6/9) or diet-induced obesity models. Searches across PubMed and Dimensions (April 2026) identified seven eligible experimental trials. Results suggest that postbiotic Bifidobacterium animalis subsp. lactis CECT 8145 reduced postprandial glucose AUC by 6 % strictly during energy restriction. Pasteurized Akkermansia muciniphila postbiotics limited diet-induced weight gain, though glucoregulatory impacts were highly strain-specific (AKK2 reduced fasting glucose and insulin resistance indexes, whereas EB-AMDK19 exerted no significant effect). Specific probiotics (including Enterococcus faecium, Bifidobacterium lactis, Lactiplantibacillus plantarum and Bifidobacterium breve) attenuated fasting hyperinsulinemia and preserved circulating adiponectin, but lipid profile improvements (triglycerides and total cholesterol) were inconsistent across trials. In dogs, increased luminal short-chain fatty acids are not consistently mirrored by endocrine responses, so the coupling between microbial metabolites and incretin signaling remains incomplete. A critical lack of standardized reporting for species-validated insulin sensitivity metrics was identified. In conclusion, microbiome-targeted therapies, particularly inanimate postbiotics, may represent useful adjunctive strategies to mitigate metabolic dysregulation in obesogenic environments. However, clinical efficacy remains strictly strain-specific and dependent on host energy balance. Given the scarcity of high-certainty evidence, future trials must integrate dynamic physiological assessments with species-validated surrogate indexes alongside standardized dietary controls.

Animals↗
PubMed2025

Targeting hepatocyte-specific SLC2A8 blocks hepatic steatosis and dissociates TCA cycle flux inhibition from glutamine anaplerosis.

BACKGROUND: Excess TCA cycle and glutamine anaplerosis are hallmarks of metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Blocking glutamine metabolism attenuates metabolic dysfunction-associated steatohepatitis. However, inhibiting TCA cycle flux by blocking plasma membrane carbohydrate transport is limited by the ubiquitous tissue distribution, function, and homology among the SLC2A family of facilitative carbohydrate transporters, and the potential for carbohydrate blockade to invoke or exacerbate glutamine anaplerosis. Here, we quantify alterations in hepatocyte carbon flux, define the broader metabolic consequences of hepatocyte-specific GLUT8/SLC2A8 inhibition, and delineate the antisteatotic efficacy of a novel small-molecule GLUT8-selective inhibitor. METHODS: We generated mice with floxed SLC2A8 alleles and expressed hepatocyte-specific Cre by breeding these mice with albumin-Cre transgenic mice, or by administering AAV8 encoding hepatocyte-specific iCre. We performed stable-isotope glucose, fructose, and glutamine metabolic labeling in isolated GLUT8WT and GLUT8LKO hepatocytes and performed metabolic phenotyping in lean and diet-induced obese GLUT8WT and GLUT8LKO mice. Finally, we performed high-throughput screening to identify a GLUT8-selective inhibitor, which we characterized using in vitro models of triglyceride accumulation. RESULTS: Hepatocyte-specific SLC2A8 deletion reduced diet-induced hepatic and peripheral fat accumulation and increased thermogenesis during ZT12-24 (eg, the dark phase). It also disrupted TCA cycle flux without inducing compensatory glutamine utilization. High-throughput screening identified a small-molecule, GLUT8-selective inhibitor, P20, which blocked hepatocyte TG accumulation and inflammation in in vitro steatotic and inflammatory models. CONCLUSIONS: Deleting the hepatocyte carbohydrate transporter GLUT8 suppresses TCA cycle flux without inducing compensatory glutamine anaplerosis. The net effect of this is liver protection against multiple forms of dietary insult. Given that selective pharmacological GLUT8 inhibition is feasible, GLUT8 may be a viable target to abate metabolic dysfunction-associated steatohepatitis and other complications of obesity.

Animals↗
PubMed2025

GHSR suppression in neurons protects against aging-associated metabolic and cognitive impairments.

Aging is accompanied by progressive declines in metabolic and cognitive functions. Growth hormone secretagogue receptor (GHSR), a receptor for the gut hormone ghrelin, is highly expressed in neurons and plays a crucial role in metabolic regulation. We previously reported that aged global GHSR-ablated mice are lean and insulin-sensitive, and that neuronal GHSR-deleted mice (Syn1-cre;Ghsrf/f) completely prevent diet-induced obesity. However, the role of neuronal GHSR in metabolic and cognitive aging has not been elucidated. The current study aims to determine the roles of neuronal GHSR in aging metabolism and cognitive dysfunction. Syn1-cre;Ghsrf/f mice were subjected to cold stress, glucose- and insulin-tolerance tests, behavioral tests, and tissue analysis. Aging is accompanied by glycemic dysregulation and insulin resistance; old Syn1-cre;Ghsrf/f mice showed improved glucose tolerance and insulin sensitivity. Aging is associated with thermogenic impairment and cognitive decline; old Syn1-cre;Ghsrf/f mice showed better cold resistance and retained better recognition memory. Noticeably, there were increased expression of thermogenic makers (PGC1α and UCP1) and elevated sympathetic innervation markers (tyrosine hydroxylase and synaptophysin) in brown adipose tissue of old Syn1-cre;Ghsrf/f mice. Lastly, old Syn1-cre;Ghsrf/f mice exhibited decreased pro-inflammatory cytokines and increased neural plasticity-related markers (brain-derived neurotrophic factor, synaptophysin, and tyrosine hydroxylase) in metabolic and cognitive-relevant brain regions such as hypothalamus, cortex, and hippocampus. In conclusion, neuronal inhibition of GHSR promotes a healthy aging phenotype showing improved energy metabolism and cognitive function, which is likely contributed to the improved thermogenesis and insulin sensitivity, reduced inflammation, and restored neuronal plasticity.

Animals↗
PubMed2026

The novel adipokine Placin regulates glucose homeostasis via insulin secretion and IGF1 receptor signaling.

While genome-wide association studies have linked the human PLAC9 gene to body mass index, its physiological function remains largely unexplored. This study identifies PLAC9 as a novel adipokine that is enriched in the stromal vascular fraction of adipose tissue. Its circulating levels correlate with key metabolic dysregulation markers in humans and mice. We utilized gain- and loss-of-function approaches in diet-induced obesity (DIO) and streptozotocin (STZ)-induced diabetic mouse models to demonstrate that PLAC9 is a critical regulator of systemic metabolism. Notably, knockdown of endogenous PLAC9 exacerbated metabolic impairments, while its overexpression significantly mitigated DIO-associated metabolic dysregulation. Additionally, recombinant PLAC9 protein administration alleviated hyperglycemia in insulin-resistant and insulin-deficient models. Mechanistically, PLAC9 potentiated calcium-dependent insulin secretion in pancreatic beta cells, promoted glucose uptake in the liver and skeletal muscle, and upregulated hepatic Ghr and Igf1 levels to facilitate glucose homeostasis. Based on these hormone-like properties, we propose renaming the protein Placin. Collectively, these findings establish Placin as a promising therapeutic target, offering translational potential for the management of both type 2 and type 1 diabetes.

Animals↗
PubMed2026

Loss of Mtarc1 Protects Against Steatotic Liver Disease in Mice.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) spans from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and can progress to cirrhosis or hepatocellular carcinoma. Despite its prevalence, effective therapies are lacking. Recent genome-wide association studies identified a common missense variant (rs2642438) in the Mitochondrial Amidoxime Reducing Component 1 (MTARC1) gene that protects against liver cirrhosis without increasing cardiovascular disease risk. Biochemical and disease risk signatures associated with carriers of this missense variant also aligned with those of a known loss-of-function MTARC1 variant, suggesting mARC1 inhibition as a potential MASLD treatment. METHODS: To validate mARC1 loss-of-function as protective against MASLD, we generated Mtarc1 knockout (KO) mice and placed them on a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Effects of Mtarc1 KO on obesity and type 2 diabetes were explored using a high-fat diet. Hepatocytes from Mtarc1 KO mice were isolated to explore the molecular mechanisms by which Mtarc1 KO impacts lipid metabolism. RESULTS: Mtarc1 KO mice exhibited no vital growth or development defects. With a high-fat diet-induced obesity model, obese Mtarc1 KO mice exhibited reduced liver mass and lower cholesterol levels, with no effect on glucose homeostasis. In a CDAHFD-induced MASLD model, mARC1 deficiency significantly reduced liver steatosis, profibrosis, and inflammation. Untargeted metabolomics profiling further showed hepatic enrichment of phospholipids in Mtarc1 KO mice. Primary hepatocytes isolated from Mtarc1 KO mice exhibited reduced lipid droplet accumulation, decreased fatty acid uptake, and increased lipid secretion. CONCLUSIONS: These findings support mARC1 inhibition as a promising therapeutic strategy for MASLD/MASH.

Animals↗
PubMed2026

Changes in weight and metabolic health during and after cessation of a time-restricted feeding plus aerobic training in Swiss mice fed a high-fat diet.

Obesity is a chronic disease, representing a significant health problem worldwide. Unhealthy eating habits and sedentarism are key contributors to the development of obesity. Dietary and exercise strategies are the first-line therapies for weight loss or maintenance and have proven effective in controlling weight. However, long-term adherence is challenging, and rapid weight regain often follows intervention cessation. In mice, time-restricted feeding (TRF) and exercise (EXE) independently prevent weight gain and maintain metabolic health, yet weight regain is observed upon cessation. Whether combining TRF and EXE provides longer-lasting benefits remains unclear. Here, we assessed weight and metabolic parameters in Swiss male mice fed with a high-fat diet (HFD) during an 8-wk intervention of TRF (8-h food access in the active phase) or TRF combined with EXE (60-min treadmill running daily) and after cessation and transfer to ad libitum feeding. TRF and EXE interventions successfully mitigate weight gain, improve glycemic homeostasis, and attenuate lipid accumulation in the liver and adipose tissue hypertrophy compared to mice fed HFD ad libitum. However, cessation of both strategies led to rapid weight regain, impaired glycemic control, and increased circulating lipid levels. Although the combination of TRF and EXE led to the lowest body weight and best metabolic health, this group showed no protection against the metabolic impairments observed after TRF cessation alone. In conclusion, TRF and EXE are complementary strategies for managing metabolic health, but cessation of these interventions leads to rapid weight regain and metabolic deterioration, with only partial preservation of select metabolic adaptations. These findings underscore the critical need for sustained adherence to lifestyle interventions in obesity management.NEW & NOTEWORTHY This study demonstrates that combining time-restricted feeding with aerobic training improves weight and metabolic health in Swiss mice fed a high-fat diet. Importantly, we show that most metabolic benefits are lost after intervention cessation. However, insulin sensitivity and aspects of hepatic lipid metabolism are partially maintained after cessation of the intervention. These findings provide new insight into the durability of metabolic improvements induced by lifestyle interventions and highlight the potential of combined dietary and exercise strategies to counteract diet-induced obesity and metabolic dysfunction.

Animals↗
PubMed2026

Adipocyte-derived CRAMP-neutrophil serine protease interaction axis regulates innate cutaneous defense against Staphylococcus aureus.

Dermal adipocytes have emerged as active participants in cutaneous host defense. In parallel, adipocyte hypertrophy and hyperplasia-driven obesity has become a global public health priority and is strongly associated with increased risk and severity of bacterial infections. Here, we established and optimized two complementary S. aureus infection models-epidermal and subcutaneous-and in combination with diet-induced (HFD) and genetic (ob/ob) obesity, to systematically evaluate cathelin-related antimicrobial peptide (CRAMP) expression in adipocytes and its crosstalk with neutrophils. Obese mice displayed impaired cutaneous defense despite marked thickening of the fat layer, characterized by attenuated induction of adipocyte CRAMP and reduced local antibacterial activity. In vitro, CRAMP followed a biphasic pattern during adipocyte differentiation-upregulated at early stages but diminished with advanced maturation and lipid accumulation. Mechanistically, neutrophils processed adipocyte-derived CRAMP via serine proteases to generate shorter peptides with enhanced antibacterial activity. Collectively, these findings identify a CRAMP-neutrophil (serine protease) interaction axis as a key amplifier of cutaneous innate immunity and provide mechanistic insight into obesity-associated susceptibility to skin infection, suggesting potential avenues for targeted intervention.

Animals↗
PubMed2025

C6ORF120 regulates hepatic lipid metabolism through PPAR signaling pathway in metabolic dysfunction-associated steatotic liver disease.

Background Emerging evidence indicates that C6ORF120 is highly expressed in the liver and may modulate immune responses in various hepatic disorders. However, its role in hepatic lipid metabolism and metabolic dysfunction-associated steatotic liver disease (MASLD) is unexplored. This study aimed to elucidate the effects and potential mechanisms of C6ORF120 on hepatic lipogenesis. Methods C6ORF120 expression in MASLD was assessed using patient serum and the Gene Expression Omnibus (GEO) database. A high-fat diet-induced MASLD model was established in C6orf120-KO rats. Fatty acid-induced lipid accumulation models were generated in primary hepatocytes, HepG2 and Huh7 cells. These models were employed to investigate the effects of C6ORF120 on hepatic lipogenesis and MASLD progression. Results C6ORF120 expression was significantly upregulated in MASLD patients and obese rat models. Genetic deletion of C6ORF120 markedly alleviated high-fat diet-induced steatosis in the liver of rats. In vitro, C6orf120 gene deficiency attenuated lipid accumulation and suppressed key lipogenic genes (such as fatty acid synthase (Fasn), phospho-acetyl coenzyme carboxylase (p-ACC), sterol regulatory element binding protein-1c (Srebp1c)) in primary hepatocytes and HepG2 cells. Conversely, C6ORF120 overexpression increased lipid accumulation in HepG2 cells. RNA sequencing analysis showed that lipid metabolism pathway and peroxisome proliferators activated receptor (PPAR) signaling pathway were significantly altered in the liver of C6orf120-KO rats. We demonstrated that C6ORF120 may regulate lipid metabolism through the hepatic PPARα, which is involved in fatty acid production and lipid oxidation. Further, we found that serum C6ORF120 expression was correlated with clinical indicators in patients with MASLD. Conclusion This study preliminarily revealed a novel function for C6ORF120 in hepatic lipid metabolism via affecting the PPAR pathway. The result identifies C6ORF120 as a novel regulator of hepatic lipid metabolism through PPARα-dependent mechanisms, offering potential therapeutic targets for MASLD.

Lipid Metabolism↗
PubMed2024

Whole transcriptome sequencing analyses of islets reveal ncRNA regulatory networks underlying impaired insulin secretion and increased β-cell mass in high fat diet-induced diabetes mellitus.

AIM: Our study aims to identify novel non-coding RNA-mRNA regulatory networks associated with β-cell dysfunction and compensatory responses in obesity-related diabetes. METHODS: Glucose metabolism, islet architecture and secretion, and insulin sensitivity were characterized in C57BL/6J mice fed on a 60% high-fat diet (HFD) or control for 24 weeks. Islets were isolated for whole transcriptome sequencing to identify differentially expressed (DE) mRNAs, miRNAs, IncRNAs, and circRNAs. Regulatory networks involving miRNA-mRNA, lncRNA-mRNA, and lncRNA-miRNA-mRNA were constructed and functions were assessed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. RESULTS: Despite compensatory hyperinsulinemia and a significant increase in β-cell mass with a slow rate of proliferation, HFD mice exhibited impaired glucose tolerance. In isolated islets, insulin secretion in response to glucose and palmitic acid deteriorated after 24 weeks of HFD. Whole transcriptomic sequencing identified a total of 1324 DE mRNAs, 14 DE miRNAs, 179 DE lncRNAs, and 680 DE circRNAs. Our transcriptomic dataset unveiled several core regulatory axes involved in the impaired insulin secretion in HFD mice, such as miR-6948-5p/Cacna1c, miR-6964-3p/Cacna1b, miR-3572-5p/Hk2, miR-3572-5p/Cckar and miR-677-5p/Camk2d. Additionally, proliferative and apoptotic targets, including miR-216a-3p/FKBP5, miR-670-3p/Foxo3, miR-677-5p/RIPK1, miR-802-3p/Smad2 and ENSMUST00000176781/Caspase9 possibly contribute to the increased β-cell mass in HFD islets. Furthermore, competing endogenous RNAs (ceRNA) regulatory network involving 7 DE miRNAs, 15 DE lncRNAs and 38 DE mRNAs might also participate in the development of HFD-induced diabetes. CONCLUSIONS: The comprehensive whole transcriptomic sequencing revealed novel non-coding RNA-mRNA regulatory networks associated with impaired insulin secretion and increased β-cell mass in obesity-related diabetes.

Mice↗
PubMedDate not supplied

Effects of fat mass reduction by dieting and by lipectomy on carbohydrate metabolism in obese patients.

The interrelation of enlarged body fat mass (BFM) with reduced carbohydrate tolerance and hyperinsulinemia was studied in obese subjects with chemical diabetes. These patients were subjected to lipectomy following weight loss induced by a low-calorie, low-carbohydrate diet. An improvement in glucose tolerance and in insulin sensitivity and a reduction in insulin release during OGTT was observed after a diet-induced BFM loss of 9.9 +/-1.2 kg. Subsequent surgical reduction of BFM by 6.0 +/- 0.5 kg had no further effect upon carbohydrate tolerance, insulin release or insulin sensitivity though a marked decrease in basal plasma FFA values was observed. These findings suggest that fat mass enlargement per se has no effect on blood glucose homeostasis after oral or i.v. loading. The improvement in carbohydrate tolerance and in insulin resistance usually observed following diet-induced loss of BFM seems to be due to the reduction in calorie and carbohydrate intake rather than to decrease of BFM.

Adipose Tissue↗