scholarly journals CX3CL1 action on microglia protects from diet-induced obesity by restoring POMC neuronal excitability and melanocortin system activity impaired by high-fat diet feeding

2021 ◽  
Author(s):  
Jineta Banerjee ◽  
Mauricio D. Dorfman ◽  
Rachael Fasnacht ◽  
John D. Douglass ◽  
Alice C. Wyse-Jackson ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Microglial Activation ◽  
Molecular Mechanisms ◽  
Melanocortin Receptor ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity ◽  
Neuron Excitability ◽  
Melanocortin Signaling

Objective: Diet-induced obesity (DIO) is associated with hypothalamic microglial activation and dysfunction of the melanocortin pathway, but the molecular mechanisms linking the two remain unclear. Previous studies have hypothesized that microglial inflammatory signaling is linked with impaired pro-opiomelanocortin (POMC) neuron function, but this mechanism has never been directly tested in vivo. We addressed this hypothesis using the specific microglial silencing molecule, CX3CL1 (fractalkine), to determine whether reducing hypothalamic microglial activation can restore POMC/melanocortin signaling in the brain to protect against DIO. Methods: We performed metabolic analyses in mice with targeted viral overexpression of CX3CL1 in the hypothalamus exposed to high fat diet (HFD). Electrophysiologic recording in hypothalamic slices from POMC-MAPT-GFP mice was used to determine the effects of HFD feeding and microglial silencing via minocycline or CX3CL1 on GFP-labeled POMC neurons. Finally, mice with hypothalamic overexpression of CX3CL1 received central treatment with the melanocortin receptor antagonist SHU-9119 to determine whether melanocortin signaling is required for the metabolic benefits of CX3CL1. Results: We found that targeted expression of both soluble and membrane-bound forms of CX3CL1 in the mediobasal hypothalamus potently reduced weight gain and increased leptin sensitivity in animals exposed to high fat diet. The protective effect of CX3CL1 rescued diet-induced changes in POMC neuron excitability and required intact melanocortin receptor signaling in vivo. Conclusion: Our results provide the first evidence that HFD-induced POMC neuron dysfunction involves microglial activation. Furthermore, our study suggests that the anti-obesity action of CX3CL1 is mediated through the restoration of POMC neuron excitability and melanocortin signaling.

scholarly journals Deficiency of Growth Differentiation Factor 3 Protects against Diet-Induced Obesity by Selectively Acting on White Adipose

2009 ◽  
Vol 23 (1) ◽  
pp. 113-123 ◽  
Author(s):  
Joseph J. Shen ◽  
Lihua Huang ◽  
Liunan Li ◽  
Carolina Jorgez ◽  
Martin M. Matzuk ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Normal Weight ◽  
Metabolic Rates ◽  
Wild Type ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Differentiation Factor ◽  
Tgfβ Superfamily

Growth differentiation factor 3 (GDF3) is a member of the TGFβ superfamily. White adipose is one of the tissues in which Gdf3 is expressed, and it is the only tissue in which expression increases in response to high-fat diet. We generated Gdf3−/− mice, which were indistinguishable from wild-type mice and had normal weight curves on regular diet. However, on high-fat diet Gdf3−/− mice were resistant to the obesity that normally develops in wild-type mice. Herein we investigate the physiological and molecular mechanisms that underlie this protection from diet-induced obesity and demonstrate that GDF3 deficiency selectively affects white adipose through its influence on basal metabolic rates. Our results are consistent with a role for GDF3 in adipose tissue, with consequential effects on energy expenditure that ultimately impact adiposity.

scholarly journals CTRP9 transgenic mice are protected from diet-induced obesity and metabolic dysfunction

2013 ◽  
Vol 305 (5) ◽  
pp. R522-R533 ◽  
Author(s):  
Jonathan M. Peterson ◽  
Zhikui Wei ◽  
Marcus M. Seldin ◽  
Mardi S. Byerly ◽  
Susan Aja ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Transgenic Mice ◽  
High Fat Diet ◽  
Fat Oxidation ◽  
Acid Oxidation ◽  
Ampk Activation ◽  
High Fat ◽  
Diet Induced Obesity

CTRP9 is a secreted multimeric protein of the C1q family and the closest paralog of the insulin-sensitizing adipokine, adiponectin. The metabolic function of this adipose tissue-derived plasma protein remains largely unknown. Here, we show that the circulating levels of CTRP9 are downregulated in diet-induced obese mice and upregulated upon refeeding. Overexpressing CTRP9 resulted in lean mice that dramatically resisted weight gain induced by a high-fat diet, largely through decreased food intake and increased basal metabolism. Enhanced fat oxidation in CTRP9 transgenic mice resulted from increases in skeletal muscle mitochondrial content, expression of enzymes involved in fatty acid oxidation (LCAD and MCAD), and chronic AMPK activation. Hepatic and skeletal muscle triglyceride levels were substantially decreased in transgenic mice. Consequently, CTRP9 transgenic mice had a greatly improved metabolic profile with markedly reduced fasting insulin and glucose levels. The high-fat diet-induced obesity, insulin resistance, and hepatic steatosis observed in wild-type mice were prevented in transgenic mice. Consistent with the in vivo data, recombinant protein significantly enhanced fat oxidation in L6 myotubes via AMPK activation and reduced lipid accumulation in H4IIE hepatocytes. Collectively, these data establish CTRP9 as a novel metabolic regulator and a new component of the metabolic network that links adipose tissue to lipid metabolism in skeletal muscle and liver.

SIRT6 in mouse spermatogenesis is modulated by diet-induced obesity

2011 ◽  
Vol 23 (7) ◽  
pp. 929 ◽  
Author(s):  
Nicole O. Palmer ◽  
Tod Fullston ◽  
Megan Mitchell ◽  
Brian P. Setchell ◽  
Michelle Lane
Keyword(s):  
Dna Damage ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Control Diet ◽  
Male Mice ◽  
High Fat ◽  
Sperm Dna Damage ◽  
Diet Induced Obesity ◽  
Damage Repair ◽  
Sperm Dna

Male obesity is associated with reduced sperm function and increased incidence of sperm DNA damage; however, the underlying molecular mechanisms have not yet been identified. Mammalian SIRT6 protein is involved in caloric-dependant DNA damage repair in other tissue types, yet a possible role for SIRT6 in male obesity and subfertility has not been investigated previously. To assess SIRT6 levels and activity in the testes, male mice (n = 12 per diet) were fed either a control diet (CD; 6% fat) or a high-fat diet (HFD; 21% fat) for 16 weeks before the collection of testes and spermatozoa. SIRT6 protein was localised to the nucleus of transitional spermatids and the acrosome of mature spermatozoa, with levels significantly decreased in HFD-fed male mice (P < 0.05). This decrease in SIRT6 protein was associated with transitional spermatids having increased levels of acetylated H3K9 in the nucleus (P < 0.01) and increased DNA damage (P < 0.001). We propose a role for SIRT6 in spermiogenesis and potentially protamination processes, which are known to be compromised by male obesity.

scholarly journals Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons

2011 ◽  
Vol 301 (1) ◽  
pp. E187-E195 ◽  
Author(s):  
Guillaume de Lartigue ◽  
Claire Barbier de la Serre ◽  
Elvis Espero ◽  
Jennifer Lee ◽  
Helen E. Raybould
Keyword(s):  
High Fat Diet ◽  
Leptin Resistance ◽  
Afferent Neurons ◽  
High Fat ◽  
Leptin Signaling ◽  
Protein Levels ◽  
Diet Induced Obesity ◽  
Nodose Ganglia ◽  
Vagal Afferent

Ingestion of high-fat, high-calorie diets is associated with hyperphagia, increased body fat, and obesity. The mechanisms responsible are currently unclear; however, altered leptin signaling may be an important factor. Vagal afferent neurons (VAN) integrate signals from the gut in response to ingestion of nutrients and express leptin receptors. Therefore, we tested the hypothesis that leptin resistance occurs in VAN in response to a high-fat diet. Sprague-Dawley rats, which exhibit a bimodal distribution of body weight gain, were used after ingestion of a high-fat diet for 8 wk. Body weight, food intake, and plasma leptin levels were measured. Leptin signaling was determined by immunohistochemical localization of phosphorylated STAT3 (pSTAT3) in cultured VAN and by quantifaction of pSTAT3 protein levels by Western blot analysis in nodose ganglia and arcuate nucleus in vivo. To determine the mechanism of leptin resistance in nodose ganglia, cultured VAN were stimulated with leptin alone or with lipopolysaccharide (LPS) and SOCS-3 expression measured. SOCS-3 protein levels in VAN were measured by Western blot following leptin administration in vivo. Leptin resulted in appearance of pSTAT3 in VAN of low-fat-fed rats and rats resistant to diet-induced obesity but not diet-induced obese (DIO) rats. However, leptin signaling was normal in arcuate neurons. SOCS-3 expression was increased in VAN of DIO rats. In cultured VAN, LPS increased SOCS-3 expression and inhibited leptin-induced pSTAT3 in vivo. We conclude that VAN of diet-induced obese rats become leptin resistant; LPS and SOCS-3 may play a role in the development of leptin resistance.

scholarly journals High-Fat Diet Alters the Expression of Reference Genes in Male Mice

2020 ◽  
Vol 7 ◽  
Author(s):  
Xiuqin Fan ◽  
Hongyang Yao ◽  
Xuanyi Liu ◽  
Qiaoyu Shi ◽  
Liang Lv ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Reference Genes ◽  
Molecular Mechanisms ◽  
Obese Mouse ◽  
Mrna Levels ◽  
High Fat ◽  
Adipose Tissues ◽  
Obesity Epidemic ◽  
Diet Induced Obesity

Quantitative PCR (qPCR), the most accurate and sensitive technique for quantifying mRNA expression, and choice of appropriate reference genes for internal error controlling in qPCR are essential to understanding the molecular mechanisms that drive the obesity epidemic and its comorbidities. In this study, using the high-fat diet (HFD)-induced obese mouse model, we assessed the expression of 10 commonly used reference genes to validate gene-expression stability in adipose tissue, liver, and muscle across different time points (4, 8, 12, and 16 weeks after HFD feeding) during the process of obesity. The data were analyzed by the GeNorm, NormFinder, BestKeeper, and Delta-Ct method, and the results showed that the most stable reference genes were different for a specific organ or tissue in a specific time point; however, PPIA, RPLP0, and YWHAZ were the top three most stable reference genes in qPCR experiments on adipose, hepatic tissues, and muscles of mice in diet-induced obesity. In addition, the mostly used genes ACTB and GAPDH were more unstable in the fat and liver, the ACTB mRNA levels were increased in four adipose tissues, and the GAPDH mRNA levels were decreased in four adipose tissues and liver after HFD feeding. These results suggest that PPIA, RPLP0, or YWHAZ may be more appropriate to be used as reference gene than ACTB and GAPDH in the adipose tissue and liver of mice during the process of high-fat diet-induced obesity.

scholarly journals GABA transporter sustains IL-1β production in macrophages

2021 ◽  
Vol 7 (15) ◽  
pp. eabe9274
Author(s):  
Yaoyao Xia ◽  
Fang He ◽  
Xiaoyan Wu ◽  
Bie Tan ◽  
Siyuan Chen ◽  
...  
Keyword(s):  
Immune Responses ◽  
High Fat Diet ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
High Fat ◽  
Gaba Transporter ◽  
Host Immune Responses ◽  
Diet Induced Obesity

Accumulating evidence shows that nervous system governs host immune responses; however, how γ-aminobutyric acid (GABA)ergic system shapes the function of innate immune cells is poorly defined. Here, we demonstrate that GABA transporter (GAT2) modulates the macrophage function. GAT2 deficiency lowers the production of interleukin-1β (IL-1β) in proinflammatory macrophages. Mechanistically, GAT2 deficiency boosts the betaine/S-adenosylmethionine (SAM)/hypoxanthine metabolic pathway to inhibit transcription factor KID3 expression through the increased DNA methylation in its promoter region. KID3 regulates oxidative phosphorylation (OXPHOS) via targeting the expression of OXPHOS-related genes and is also critical for NLRP3–ASC–caspase-1 complex formation. Likewise, GAT2 deficiency attenuates macrophage-mediated inflammatory responses in vivo, including lipopolysaccharide-induced sepsis, infection-induced pneumonia, and high-fat diet-induced obesity. Together, we propose that targeting GABAergic system (e.g., GABA transporter) could provide previously unidentified therapeutic opportunities for the macrophage-associated diseases.

scholarly journals Effects of Mogrosides on High-Fat-Diet-Induced Obesity and Nonalcoholic Fatty Liver Disease in Mice

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 1894 ◽  
Author(s):  
Xiaobing Zhang ◽  
Yunfei Song ◽  
Yipei Ding ◽  
Wei Wang ◽  
Ling Liao ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
High Purity ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Molecular Mechanisms ◽  
High Fat ◽  
Nonalcoholic Fatty Liver ◽  
Diet Induced Obesity

Obesity and nonalcoholic fatty liver disease (NAFLD) are highly prevalent and cause numerous metabolic diseases. However, drugs for the prevention and treatment of obesity and NAFLD remain unavailable. In this study, we investigated the effects of mogrosides (luo han guo, LH) in Siraitia grosvenorii saponins on high-fat-diet-induced obesity and NAFLD in mice. We found that compared with the negative control, LH reduced body and liver weight. LH also decreased fat accumulation and increased AMP-activated protein kinase (AMPK) phosphorylation (pAMPK) levels in mouse livers. We also found that high-purity mogroside V upregulated pAMPK expression in HepG2 cells. In addition, high-purity mogroside V inhibited reactive oxygen species production and upregulated sequestosome-1 (SQSTM1, p62) expression in THP-1 cells. These results suggest that LH may affect obesity and NAFLD by enhancing fat metabolism and antioxidative defenses. Mogroside V may be a main component of LH. However, the exact molecular mechanisms and active components responsible for the inhibitory effects of LH on obesity and NAFLD require further investigation.

A more pronounced effect of type III resistant starch vs. type II resistant starch on ameliorating hyperlipidemia in high fat diet-fed mice is associated with its supramolecular structural characteristics

2020 ◽  
Vol 11 (3) ◽  
pp. 1982-1995 ◽  
Author(s):  
Jiangbin Xu ◽  
Zhen Ma ◽  
Xiaoping Li ◽  
Liu Liu ◽  
Xinzhong Hu
Keyword(s):  
Resistant Starch ◽  
High Fat Diet ◽  
Supramolecular Structure ◽  
Structural Characteristics ◽  
Pronounced Effect ◽  
Type Ii ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Relationship Of

The anti-obesity effects of two categories of lentil resistant starch (RS) including RS2 and RS3 on mice with high-fat diet-induced obesity and the supramolecular structure-in vivo physiological functionality relationship of RS were investigated.

Antagonism of peroxisome proliferator-activated receptor γ prevents high-fat diet-induced obesity in vivo

2006 ◽  
Vol 72 (1) ◽  
pp. 42-52 ◽  
Author(s):  
Ryosuke Nakano ◽  
Eiji Kurosaki ◽  
Shigeru Yoshida ◽  
Masanori Yokono ◽  
Akiyoshi Shimaya ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Diet Induced Obesity

scholarly journals Alterations of calcium channels and cell excitability in intracardiac ganglion neurons from type 2 diabetic rats

2012 ◽  
Vol 302 (8) ◽  
pp. C1119-C1127 ◽  
Author(s):  
Jinxu Liu ◽  
Huiyin Tu ◽  
Hong Zheng ◽  
Libin Zhang ◽  
Thai P. Tran ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Arterial Baroreflex ◽  
High Fat ◽  
Patch Clamp Technique ◽  
Cell Excitability ◽  
Neuron Excitability ◽  
Ganglion Neurons

Clinical study has demonstrated that patients with type 2 diabetes with attenuated arterial baroreflex have higher mortality rate compared with those without arterial baroreflex dysfunction. As a final pathway for the neural control of the cardiac function, functional changes of intracardiac ganglion (ICG) neurons might be involved in the attenuated arterial baroreflex in the type 2 diabetes mellitus (T2DM). Therefore, we measured the ICG neuron excitability and Ca2+ channels in the sham and T2DM rats. T2DM was induced by a combination of both high-fat diet and low-dose streptozotocin (STZ, 30 mg/kg ip) injection. After 12–14 wk of the above treatment, the T2DM rats presented hyperglycemia, hyperlipidemia, and insulin resistance but no hyperinsulinemia, which closely mimicked the clinical features of the patients with T2DM. Data from immunofluorescence staining showed that L, N, P/Q, and R types of Ca2+ channels were expressed in the ICG neurons, but only protein expression of N-type Ca2+ channels was decreased in the ICG neurons from T2DM rats. Using whole cell patch-clamp technique, we found that T2DM significantly reduced the Ca2+ currents and cell excitability in the ICG neurons. ω-Conotoxin GVIA (a specific N-type Ca2+ channel blocker, 1 μM) lowered the Ca2+ currents and cell excitability toward the same level in sham and T2DM rats. These results indicate that the decreased N-type Ca2+ channels contribute to the suppressed ICG neuron excitability in T2DM rats. From this study, we think high-fat diet/STZ injection-induced T2DM might be an appropriate animal model to test the cellular and molecular mechanisms of cardiovascular autonomic dysfunction.

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