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Endocrinology Jun 2024Thyroid hormone (TH) plays a crucial role in regulating the functions of both bone and adipose tissue. Given that TH exerts its cholesterol-lowering effects in hepatic...
Thyroid hormone (TH) plays a crucial role in regulating the functions of both bone and adipose tissue. Given that TH exerts its cholesterol-lowering effects in hepatic tissue through the TH receptor-β (TRβ), we hypothesized that TRβ agonist therapy using MGL3196 (MGL) would be effective in treating increased adiposity and bone loss in response to a 12-week high-fat diet (HFD) in adult C57BL/6J mice. Transcriptional and serum profiling revealed that HFD-induced Leptin promoted weight gain in both males and females, but MGL only suppressed Leptin induction and weight gain in males. In vitro studies suggest estrogen suppresses MGL activity in adipocytes, indicating estrogen might interfere with MGL-TRβ function. Compared to systemic adiposity, HFD reduced bone mass in male but not female mice. Paradoxically, MGL treatment reversed macroscopic BMD loss in appendicular bones, but micro-CT revealed that MGL exacerbated HFD-induced trabecular bone loss, and bone strength. In studies on the mechanisms for HFD effects on bone, we found that HFD induced Rankl expression in male femurs that was blocked by MGL. By ex vivo assays, we found that RANKL indirectly represses osteoblast lineage allocation of osteoprogenitors by induction of inflammatory cytokines TNFα, Il-1β, and CCL2. Finally, we found that MGL functions in both systemic adiposity and bone by nongenomic TRβ signaling, as HFD-mediated phenotypes were not rescued in TRβ147F knockout mice with normal genomic but defective nongenomic TRβ signaling. Our findings demonstrate that the negative effects of HFD on body fat and bone phenotypes is impacted by MGL in a gender-specific manner.
PubMed: 38935021
DOI: 10.1210/endocr/bqae075 -
Journal of Food and Drug Analysis Jun 2024Citrus peels contain abundant polyphenols, particularly flavonoids, and have been shown to exert lipid accumulation decreasing ability. In this study, Citrus depressa...
Citrus peels contain abundant polyphenols, particularly flavonoids, and have been shown to exert lipid accumulation decreasing ability. In this study, Citrus depressa peel applied to oven drying and extracted with ethanol extract as CDEE to analyze its flavonoids compositions and investigated its effects on a high-fat diet (HFD)-induced obese mice model. CDEE contained several flavonoids such as hesperidin, sinesentin, nobiletin, tangeretin, 5-demethylnobiletin, and 5-demethyltangeretin. The mice fed an HFD, and administration of 2% CDEE to could decrease weight gain, abdominal fat weight, inguinal fat weight, and the adipocyte size, and CDEE also reduced serum total cholesterol (TCHO), triacylglycerol (TG) compared with mice fed only on HFD. CDEE hindered lipid accumulation through a decreased fatty acid synthase (FAS) protein expression via upregulation of the protein expression of AMP-activated protein kinase α (AMPKα). Moreover, CDEE modulated gut microbiota that altered by HFD through an increased abundance of Lactobacillus reuteri compared with the HFD group. The results demonstrated that CDEE helps decrease lipid accumulation through the AMPK pathway, which also indicates a prebiotic-like effect on gut microbiota.
Topics: Animals; Gastrointestinal Microbiome; Mice; Plant Extracts; Citrus; Male; Obesity; Lipid Metabolism; Prebiotics; Mice, Inbred C57BL; Mice, Obese; Diet, High-Fat; Humans; Triglycerides; Bacteria
PubMed: 38934690
DOI: 10.38212/2224-6614.3504 -
Journal of Diabetes and Metabolic... Jun 2024Klotho is a membrane protein predominantly expressed in the kidneys, and its discovery was serendipitously made through gene-targeting experiments conducted on mice.... (Review)
Review
INTRODUCTION
Klotho is a membrane protein predominantly expressed in the kidneys, and its discovery was serendipitously made through gene-targeting experiments conducted on mice. Klotho has a favorable role in the regulation of multiple cellular processes, such as aging, oxidative stress, inflammation, and apoptosis. This regulation occurs through the targeting of diverse signaling molecules, cell membrane receptors, and ion channels, achieved by physical contacts or enzymatic activities of Klotho. This review examines the role of Klotho in the epigenetic regulation of molecules associated with diabetes.
METHODS
Authors conducted a thorough literature search using the PubMed®, Web of Science™, and Scopus®. Relevant articles up to September 2023, published in the English language were considered. We reviewed research databases searching for studies that included keywords klotho, epigenetic, and diabetes.
RESULTS
14 related papers about epigenetic modification of proteins involved in diabetes pathogenesis were selected to be included in this narrative review. In the studies, the kidney was the most investigated organ regarding this correlation. Also, phosphorylation and methylation were the common epigenetic modifications of proteins by Klotho.
CONCLUSION
Klotho has a significant role in the maturation of adipocytes and the regulation of systemic glucose metabolism, exhibiting a strong association with the pathogenesis of diabetes. Both epigenetic alterations and the modulation of protein phosphorylation by Klotho play significant roles in the regulation of Klotho expression and the modulation of other molecules implicated in the etiology of diabetes.
PubMed: 38932867
DOI: 10.1007/s40200-024-01387-6 -
Journal of Diabetes and Metabolic... Jun 2024Considering inhibition of pre-adipocyte cells differentiation in adipose tissue fibrosis, we aimed to explore whether Sirt1 and Hif-1α in pre-adipocytes have a...
PURPOSE
Considering inhibition of pre-adipocyte cells differentiation in adipose tissue fibrosis, we aimed to explore whether Sirt1 and Hif-1α in pre-adipocytes have a significant effect on fibrotic gene expression.
METHODS
3T3-L1 pre-adipocytes were transfected with SIRT1-specific siRNA, confirmed by real-time polymerase chain reaction (RT-PCR) and western blotting. Additionally, cells were treated with varying concentrations of resveratrol and sirtinol as the activator and inhibitor of Sirt1, respectively. Involvement of Hif-1α was evaluated by treatment with echinomycin. Subsequently, we assessed the gene and protein expressions related to fibrosis in the extracellular matrix of adipose tissue, including collagen VI (), lysyl oxidase (), matrix metalloproteinase-2 (), , and osteopontin () in pre-adipocytes through RT-PCR and western blot.
RESULTS
The current study demonstrated that knockdown and reduced enzyme activity significantly increased the expression of , , , , and genes in the treated 3T3-L1 cells compared to the control group. Interestingly, resveratrol significantly decreased the gene expression related to the fibrosis pathway. Inhibition of by echinomycin led to a significant reduction in , , and gene expression in the treated group compared to the control.
CONCLUSION
This study highlights that down-regulation of might be a predisposing factor in the emergence of adipose tissue fibrosis by enhancing the expression of extracellular matrix (ECM) components. Activation of , similar to suppressing of in pre-adipocytes may be a beneficial approach for attenuating fibrotic gene expression.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s40200-024-01389-4.
PubMed: 38932833
DOI: 10.1007/s40200-024-01389-4 -
Aging Cell Jun 2024Aging significantly influences cellular activity and metabolism in glucose-responsive tissues, yet a comprehensive evaluation of the impacts of aging and associated...
Aging significantly influences cellular activity and metabolism in glucose-responsive tissues, yet a comprehensive evaluation of the impacts of aging and associated cell-type responses has been lacking. This study integrates transcriptomic, methylomic, single-cell RNA sequencing, and metabolomic data to investigate aging-related regulations in adipose and muscle tissues. Through coexpression network analysis of the adipose tissue, we identified aging-associated network modules specific to certain cell types, including adipocytes and immune cells. Aging upregulates the metabolic functions of lysosomes and downregulates the branched-chain amino acids (BCAAs) degradation pathway. Additionally, aging-associated changes in cell proportions, methylation profiles, and single-cell expressions were observed in the adipose. In the muscle tissue, aging was found to repress the metabolic processes of glycolysis and oxidative phosphorylation, along with reduced gene activity of fast-twitch type II muscle fibers. Metabolomic profiling linked aging-related alterations in plasma metabolites to gene expression in glucose-responsive tissues, particularly in tRNA modifications, BCAA metabolism, and sex hormone signaling. Together, our multi-omic analyses provide a comprehensive understanding of the impacts of aging on glucose-responsive tissues and identify potential plasma biomarkers for these effects.
PubMed: 38932492
DOI: 10.1111/acel.14199 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Obesity has become a pandemic, as currently more than half a billion people worldwide are obese. The etiology of obesity is multifactorial, and combines a contribution... (Review)
Review
Obesity has become a pandemic, as currently more than half a billion people worldwide are obese. The etiology of obesity is multifactorial, and combines a contribution of hereditary and behavioral factors, such as nutritional inadequacy, along with the influences of environment and reduced physical activity. Two types of adipose tissue widely known are white and brown. While white adipose tissue functions predominantly as a key energy storage, brown adipose tissue has a greater mass of mitochondria and expresses the uncoupling protein 1 () gene, which allows thermogenesis and rapid catabolism. Even though white and brown adipocytes are of different origin, activation of the brown adipocyte differentiation program in white adipose tissue cells forces them to transdifferentiate into "beige" adipocytes, characterized by thermogenesis and intensive lipolysis. Nowadays, researchers in the field of small molecule medicinal chemistry and gene therapy are making efforts to develop new drugs that effectively overcome insulin resistance and counteract obesity. Here, we discuss various aspects of white-to-beige conversion, adipose tissue catabolic re-activation, and non-shivering thermogenesis.
PubMed: 38931457
DOI: 10.3390/ph17060790 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Obesity and its associated hepatic steatosis have become a global concern, posing numerous health hazards. Photodynamic therapy (PDT) is a unique approach that promotes...
Obesity and its associated hepatic steatosis have become a global concern, posing numerous health hazards. Photodynamic therapy (PDT) is a unique approach that promotes anti-obesity by releasing intracellular fat. Chlorin e6 (Ce6)-PDT was tested for its anti-obesity properties in male ovariectomized (OVX) beagle dogs, as well as male C57BL/6 and Balb/c mice. The 12 OVX beagles were randomly assigned to one of four groups: high-fat diet (HFD) only, Ce6 only, Ce6 + 10 min of light-emitting diode light (LED) treatment, and Ce6 + 15 min of light treatment. We assessed several parameters, such as body weight, adipose tissue morphology, serum biochemistry, and body fat content analysis by computed tomography (CT) scan in HFD-fed beagle dogs. At the end of the study period, dogs that were treated for 35 days with Ce6 and exposed to LED irradiation (660 nm) either for 10 min (Ce6 + 10 min of light) or for 15 min (Ce6 + 15 min of light) had decreased body weight, including visceral and subcutaneous fats, lower aspartate transaminase (AST)/alanine transaminase (ALT) ratios, and a reduction in the area of individual adipocytes with a concomitant increase in the number of adipocytes. Furthermore, C57BL/6 male mice following an HFD diet were effectively treated by Ce6-PDT treatment through a reduction in weight gain and fat accumulation. Meanwhile, Ce6-PDT attenuated hepatocyte steatosis by decreasing the epididymal adipose tissue and balloon degeneration in hepatocytes in HFD-fed Balb/c mice. Taken together, our results support the idea that Ce6-PDT is a promising therapeutic strategy for the recovery of obesity and obesity-related hepatic steatosis.
PubMed: 38931396
DOI: 10.3390/ph17060729 -
Pharmaceuticals (Basel, Switzerland) May 2024The prevalence of obesity, characterized by an excessive accumulation of adipose tissue and adipocyte hypertrophy, presents a major public health challenge. This study...
The prevalence of obesity, characterized by an excessive accumulation of adipose tissue and adipocyte hypertrophy, presents a major public health challenge. This study investigates the therapeutic potential of two probiotic strains, Probio65 and Probio-093, in the context of obesity. Utilizing 3T3-L1 cell-derived human adipocytes, we assessed Probio65's and Probio-093's capacity to mitigate triglyceride accumulation and influence adipocytokine production in vitro. Subsequently, an in vivo trial with male C57BL/6J mice examined the effects of both probiotic strains on adipose tissue characteristics, body weight, fat mass, and obesity-related gene expression. This study employed both live and ethanol-extracted bacterial cells. The results demonstrated significant reductions in the triglyceride deposition, body weight, and adipose tissue mass in the treated groups ( < 0.05). Furthermore, both strains modulated adipokine profiles by downregulating proinflammatory markers such as PAI-1, leptin, TNF-α, STAMP2, F4/80, resistin, and MCP-1, and upregulating the insulin-sensitive transporter GLUT4 and the anti-inflammatory adiponectin ( < 0.05). Our findings suggest that Probio65 and Probio-093 are promising agents for microbiome-targeted anti-obesity therapies, offering the effective mitigation of obesity and improvement in adipocyte function in a murine model.
PubMed: 38931347
DOI: 10.3390/ph17060676 -
Nutrients Jun 2024Obesity is increasingly prevalent worldwide and is linked to metabolic diseases, such as insulin resistance (IR) and type 2 diabetes mellitus (T2DM), due to excessive...
Obesity is increasingly prevalent worldwide and is linked to metabolic diseases, such as insulin resistance (IR) and type 2 diabetes mellitus (T2DM), due to excessive free fatty acids (FFAs). Although lifestyle changes are effective, they often prove to be insufficient as initial treatments for obesity. Additionally, while surgical and pharmacological interventions are available, they are not entirely safe or effective. Recently, interest has grown in utilizing food waste and plant-derived phenolic compounds for their health benefits, presenting a promising avenue for managing obesity and its related disorders. Indeed, many studies have examined the potential inhibitory effects of the natural extract on adipocyte differentiation and lipid accumulation. This study focused on the evaluation of the effects of standardized extracts obtained from red oranges and olive leaf waste on 3T3-L1 murine pre-adipocyte and adipocyte functionality. Red orange extract (ROE) and olive leaf extract (OLE), alone and in combination, were tested to assess their anti-obesity and anti-inflammatory effects, as well as their potential therapeutic benefits. Three in vitro models were established to investigate the effects of the extracts on (I) adipocyte differentiation; (II) mature and hypertrophic adipocytes challenged with palmitic acid (PA) and erastin (ER), respectively; and (III) erastin-induced cytotoxicity on pre-adipocytes.
Topics: Animals; Olea; Adipocytes; Plant Extracts; Mice; 3T3-L1 Cells; Plant Leaves; Cell Differentiation; Anti-Obesity Agents; Adipogenesis; Obesity
PubMed: 38931313
DOI: 10.3390/nu16121959 -
Nutrients Jun 2024Corn peptide (CP) is a short, naturally occurring, and physiologically active peptide generated from corn-protease-catalyzed hydrolysis. CP plays a role in preventing...
Corn peptide (CP) is a short, naturally occurring, and physiologically active peptide generated from corn-protease-catalyzed hydrolysis. CP plays a role in preventing obesity-related disorders, but its impact on reducing inflammation is unknown. Hence, this study examined the possible protective effects of corn peptide powder (CPP) against the harmful effects of lipopolysaccharide (LPS), with a particular emphasis on reducing oxidative damage and inflammation in adipocytes. Hence, mature 3T3-L1 adipocytes underwent exposure to 10 ng/mL LPS, with or without CPP (10 and 20 μg/mL). LPS stimulation increased reactive oxygen species and superoxide anion generation. However, this effect was reduced in a dose-dependent manner by pretreatment with CPP. CPP treatment elevated the mRNA expressions of the antioxidant enzymes manganese superoxide dismutase (mnSOD) and glutathione peroxidase 1 (Gpx1) while reducing the mRNA expressions of the cytosolic reactive oxygen species indicators p40 and p67 (NADPH oxidase 2). In addition, CPP inhibited the monocyte chemoattractant protein-1, tumor necrosis factor-alpha, Toll-like receptor 4, and nuclear factor kappa B mRNA expressions induced by LPS. These findings demonstrate that CPP may ameliorate adipocyte dysfunction by suppressing oxidative damage and inflammatory responses through a new mechanism known as Toll-like receptor 4/nuclear factor kappa B-mediated signaling.
Topics: Animals; Mice; 3T3-L1 Cells; Adipocytes; Lipopolysaccharides; Zea mays; Reactive Oxygen Species; Inflammation; Toll-Like Receptor 4; Oxidative Stress; Superoxide Dismutase; Powders; Peptides; Glutathione Peroxidase; NF-kappa B; Antioxidants; Glutathione Peroxidase GPX1; Signal Transduction; Chemokine CCL2; Tumor Necrosis Factor-alpha; Anti-Inflammatory Agents
PubMed: 38931278
DOI: 10.3390/nu16121924