scholarly journals Gpr17 deficiency in POMC neurons ameliorates the metabolic derangements caused by long-term high-fat diet feeding

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Austin M. Reilly ◽  
Shudi Zhou ◽  
Sunil K. Panigrahi ◽  
Shijun Yan ◽  
Jason M. Conley ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Energy Homeostasis ◽  
Regulatory Function ◽  
Chow Diet ◽  
Dependent Manner ◽  
Metabolic Homeostasis ◽  
High Fat ◽  
Electrophysiological Properties ◽  
Insulin Tolerance ◽  
Normal Chow

Abstract Background Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) control energy homeostasis by sensing hormonal and nutrient cues and activating secondary melanocortin sensing neurons. We identified the expression of a G protein-coupled receptor, Gpr17, in the ARH and hypothesized that it contributes to the regulatory function of POMC neurons on metabolism. Methods In order to test this hypothesis, we generated POMC neuron-specific Gpr17 knockout (PGKO) mice and determined their energy and glucose metabolic phenotypes on normal chow diet (NCD) and high-fat diet (HFD). Results Adult PGKO mice on NCD displayed comparable body composition and metabolic features measured by indirect calorimetry. By contrast, PGKO mice on HFD demonstrated a sexually dimorphic phenotype with female PGKO mice displaying better metabolic homeostasis. Notably, female PGKO mice gained significantly less body weight and adiposity (p < 0.01), which was associated with increased energy expenditure, locomotor activity, and respiratory quotient, while males did not have an overt change in energy homeostasis. Though PGKO mice of both sexes had comparable glucose and insulin tolerance, detailed analyses of liver gene expression and serum metabolites indicate that PGKO mice could have reduced gluconeogenesis and increased lipid utilization on HFD. To elucidate the central-based mechanism(s) underlying the better-preserved energy and glucose homeostasis in PGKO mice on HFD, we examined the electrophysiological properties of POMC neurons and found Gpr17 deficiency led to increased spontaneous action potentials. Moreover, PGKO mice, especially female knockouts, had increased POMC-derived alpha-melanocyte stimulating hormone and beta-endorphin despite a comparable level of prohormone POMC in their hypothalamic extracts. Conclusions Gpr17 deficiency in POMC neurons protects metabolic homeostasis in a sex-dependent manner during dietary and aging challenges, suggesting that Gpr17 could be an effective anti-obesity target in specific populations with poor metabolic control.

scholarly journals Commensal Bacteria Impact a Protozoan’s Integration into the Murine Gut Microbiota in a Dietary Nutrient-Dependent Manner

2020 ◽  
Vol 86 (11) ◽  
Author(s):  
Yanxia Wei ◽  
Jing Gao ◽  
Yanbo Kou ◽  
Liyuan Meng ◽  
Xingping Zheng ◽  
...  
Keyword(s):  
Microbial Community ◽  
High Fat Diet ◽  
Commensal Bacteria ◽  
Intestinal Microbiome ◽  
Chow Diet ◽  
Dependent Manner ◽  
High Fat ◽  
Normal Chow ◽  
Dietary Nutrient ◽  
Potential Factors

ABSTRACT Our current understanding of the host-microbiota interaction in the gut is dominated by studies focused primarily on prokaryotic bacterial communities. However, there is an underappreciated symbiotic eukaryotic protistic community that is an integral part of mammalian microbiota. How commensal protozoan bacteria might interact to form a stable microbial community remains poorly understood. Here, we describe a murine protistic commensal, phylogenetically assigned as Tritrichomonas musculis, whose colonization in the gut resulted in a reduction of gut bacterial abundance and diversity in wild-type C57BL/6 mice. Meanwhile, dietary nutrient and commensal bacteria also influenced the protozoan’s intestinal colonization and stability. While mice fed a normal chow diet had abundant T. musculis organisms, switching to a Western-type high-fat diet led to the diminishment of the protozoan from the gut. Supplementation of inulin as a dietary fiber to the high-fat diet partially restored the protozoan’s colonization. In addition, a cocktail of broad-spectrum antibiotics rendered permissive engraftment of T. musculis even under a high-fat, low-fiber diet. Furthermore, oral administration of Bifidobacterium spp. together with dietary supplementation of inulin in the high-fat diet impacted the protozoan’s intestinal engraftment in a bifidobacterial species-dependent manner. Overall, our study described an example of dietary-nutrient-dependent murine commensal protozoan-bacterium cross talk as an important modulator of the host intestinal microbiome. IMPORTANCE Like commensal bacteria, commensal protozoa are an integral part of the vertebrate intestinal microbiome. How protozoa integrate into a commensal bacterium-enriched ecosystem remains poorly studied. Here, using the murine commensal Tritrichomonas musculis as a proof of concept, we studied potential factors involved in shaping the intestinal protozoal-bacterial community. Understanding the rules by which microbes form a multispecies community is crucial to prevent or correct microbial community dysfunctions in order to promote the host’s health or to treat diseases.

scholarly journals ADAR1 deficiency protects against high-fat diet-induced obesity and insulin resistance in mice

2020 ◽  
Author(s):  
Xiaobing Cui ◽  
Jia Fei ◽  
Sisi Chen ◽  
Gaylen L. Edwards ◽  
Shi-You Chen
Keyword(s):  
Insulin Resistance ◽  
Food Intake ◽  
High Fat Diet ◽  
Peptide Yy ◽  
Tolerance Test ◽  
Chow Diet ◽  
High Fat ◽  
Blood Biochemical ◽  
Insulin Tolerance ◽  
Normal Chow

Obesity is an important independent risk factor for type 2 diabetes, cardiovascular diseases, and many other chronic diseases. The objective of this study was to determine the role of adenosine deaminase acting on RNA 1 (ADAR1) in the development of obesity and insulin resistance. Wild-type (WT) and heterozygous ADAR1-deficient (Adar1+/-) mice were fed normal chow or high-fat diet (HFD) for 12 weeks. Adar1+/- mice fed with HFD exhibited a lean phenotype with reduced fat mass compared with WT controls, although no difference was found under chow diet conditions. Blood biochemical analysis and insulin tolerance test showed that Adar1+/- improved HFD-induced dyslipidemia and insulin resistance. Metabolic studies showed that food intake was decreased in Adar1+/- mice compared with the WT mice under HFD conditions. Paired feeding studies further demonstrated that Adar1+/- protected mice from HFD-induced obesity through decreased food intake. Furthermore, Adar1+/- restored the increased ghrelin expression in stomach and the decreased serum peptide YY levels under HFD conditions. These data indicate that ADAR1 may contribute to diet-induce obesity, at least partially, through modulating the ghrelin and peptide YY expression and secretion.

scholarly journals Estrogens Protect against High-Fat Diet-Induced Insulin Resistance and Glucose Intolerance in Mice

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2109-2117 ◽  
Author(s):  
Elodie Riant ◽  
Aurélie Waget ◽  
Haude Cogo ◽  
Jean-François Arnal ◽  
Rémy Burcelin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Chow Diet ◽  
High Fat ◽  
Normal Chow ◽  
Visceral Adipose ◽  
Deficient Mice ◽  
Normal Chow Diet

Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor α (ERα), it has not been established whether this pathway could represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17β-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ERα-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-α) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ERα-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ERα pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.

scholarly journals Effect of A Polyphenol-Rich Canarium album Extract on the Composition of the Gut Microbiota of Mice Fed a High-Fat Diet

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2188 ◽  
Author(s):  
Ning-Ning Zhang ◽  
Wen-Hui Guo ◽  
Han Hu ◽  
A-Rong Zhou ◽  
Qing-Pei Liu ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
High Fat Diet ◽  
High Throughput Sequencing ◽  
Chow Diet ◽  
Microbiota Composition ◽  
High Fat ◽  
Canarium Album ◽  
Normal Chow ◽  
Gut Microbiota Composition ◽  
Medium Dose

This study investigated the influence of Canarium album extract (CAext) on intestinal microbiota composition of mice fed a high-fat diet (HFD). Kun Ming (KM) mice were fed either a normal chow diet or a HFD for six weeks. At the seventh week, HFD-fed mice were gavaged daily with saline, or a different dose of CAext for four weeks, respectively. Then, the composition of the gut microbiota was analyzed by high-throughput sequencing technology. Analysis of fecal microbial populations, grouped by phyla, showed significant increases of Firmicutes and Verrucomicrobia, but a decrease of Bacteroidetes in all CAext-fed mice. Particularly, CAext gavage in a low dose or a medium dose caused a significant increase in the proportion of Akkermansia. These findings suggested that CAext can alter the gut microbiota composition of HFD-fed mice, and had a potential prebiotic effects on Akkermansia.

Chronic high fat feeding and prolonged fasting in liver-specific ANGPTL4 knockout mice

2021 ◽  
Author(s):  
Kathryn Mary Spitler ◽  
Shwetha K Shetty ◽  
Emily M Cushing ◽  
Kelli L. Sylvers-Davie ◽  
Brandon S.J. Davies
Keyword(s):  
Glucose Tolerance ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Plasma Triglyceride ◽  
Chow Diet ◽  
Loss Of Function ◽  
High Fat ◽  
Prolonged Fasting ◽  
Normal Chow

Obesity is associated with dyslipidemia, ectopic lipid deposition and insulin resistance. In mice, the global or adipose-specific loss of function of the protein angiopoietin-like 4 (ANGPTL4) leads to decreased plasma triglyceride levels, enhanced adipose triglyceride uptake, and protection from high-fat diet-induced glucose intolerance. ANGPTL4 is also expressed highly in the liver, but the role of liver-derived ANGPTL4 is unclear. The goal of this study was to determine the contribution of hepatocyte ANGPTL4 to triglyceride and glucose homeostasis in mice during a high fat diet challenge. We generated hepatocyte-specific ANGPTL4 deficient (Angptl4LivKO) mice, fed them a 60% kCal/fat diet (HFD) for 6 months, and assessed triglyceride, liver, and glucose metabolic phenotypes. We also explored the effects of prolonged fasting on Angptl4LivKO mice. The loss of hepatocyte-derived Angptl4 led to no major changes in triglyceride partitioning or lipoprotein lipase activity compared to control mice. Interestingly, although there was no difference in fasting plasma triglyceride levels after a 6 h fast, after an 18 h fast normal chow diet fed Angptl4LivKO mice had lower triglyceride levels than control mice. On a HFD, Angptl4LivKO mice initially showed no difference in glucose tolerance and insulin sensitivity, but improved glucose tolerance emerged in these mice after 6 months on HFD. Our data suggest that hepatocyte ANGPTL4 does not directly regulate triglyceride partitioning, but that loss of liver-derived ANGPTL4 may be protective from HFD-induced glucose intolerance and influence plasma TG metabolism during prolonged fasting.

scholarly journals Pinealectomy increases thermogenesis and decreases lipogenesis

2019 ◽  
Author(s):  
Mikyung Kim ◽  
So Min Lee ◽  
Jeeyoun Jung ◽  
Yun Jin Kim ◽  
Kyo Chul Moon ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Lipid Droplets ◽  
Melatonin Receptors ◽  
Chow Diet ◽  
High Fat ◽  
Adipose Tissues ◽  
Lipogenic Genes ◽  
Sham Surgery ◽  
Normal Chow ◽  
Normal Chow Diet

AbstractThis study was designed to determine the effects of pineal gland-derived melatonin on obesity by employing rat pinealectomy (Pnx) model. After 10 weeks of high-fat diet (HFD) feeding, rats received sham or Pnx surgery followed by 10 weeks normal chow diet (NCD) feeding. Pnx decreased expressions of melatonin receptors, MTNR1A and MTNR1B, in brown (BAT) and white adipose tissues (WAT). Pnx rats showed increased insulin sensitivity compared with those that received sham surgery. Leptin levels were significantly decreased in the serum of Pnx group. In addition, Pnx stimulated thermogenic genes in BAT whereas attenuated lipogenic genes in WAT and the liver. Histologic analyses revealed marked decreased in the size of lipid droplets and increased expressions of UCP1 in BAT and attenuated lipid droplets in the sized and the number in the liver of Pnx group. In conclusion, these results in the current study suggest that Pnx increases thermogenesis in BAT and decreases lipogenesis in WAT and the liver.

scholarly journals The loss of ERE-dependent ERα signaling potentiates the effects of maternal high-fat diet on energy homeostasis in female offspring fed an obesogenic diet

2019 ◽  
Vol 11 (3) ◽  
pp. 285-296
Author(s):  
Troy A. Roepke ◽  
Ali Yasrebi ◽  
Alejandra Villalobos ◽  
Elizabeth A. Krumm ◽  
Jennifer A. Yang ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Energy Homeostasis ◽  
Female Offspring ◽  
Chow Diet ◽  
High Fat ◽  
Monocyte Chemoattractant Protein 1 ◽  
Estrogen Response ◽  
Obesogenic Diet ◽  
Liver Gene ◽  
Factor Α

AbstractMaternal high-fat diet (HFD) alters hypothalamic programming and disrupts offspring energy homeostasis in rodents. We previously reported that the loss of ERα signaling partially blocks the effects of maternal HFD in female offspring fed a standard chow diet. In a companion study, we determined if the effects of maternal HFD were magnified by an adult obesogenic diet in our transgenic mouse models. Heterozygous ERα knockout (wild-type (WT)/KO) dams were fed a control breeder chow diet (25% fat) or a semipurified HFD (45% fat) 4 weeks prior to mating with heterozygous males (WT/KO or WT/ knockin) to produce WT, ERα KO, or ERα knockin/knockout (KIKO) (no estrogen response element (ERE) binding) female offspring, which were fed HFD for 20 weeks. Maternal HFD potentiated the effects of adult HFD on KIKO and KO body weight due to increased adiposity and decreased activity. Maternal HFD also produced KIKO females that exhibit KO-like insulin intolerance and impaired glucose homeostasis. Maternal HFD increased plasma interleukin 6 and monocyte chemoattractant protein 1 levels and G6pc and Pepck liver expression only in WT mice. Insulin and tumor necrosis factor α levels were higher in KO offspring from HFD-fed dams. Arcuate and liver expression of Esr1 was altered in KIKO and WT, respectively. These data suggest that loss of ERE-dependent ERα signaling, and not total ERα signaling, sensitizes females to the deleterious influence of maternal HFD on offspring energy and glucose potentially through the control of peripheral inflammation and hypothalamic and liver gene expression. Future studies will interrogate the tissue-specific mechanisms of maternal HFD programming through ERα signaling.

scholarly journals HDAC5-mTORC1 Interaction in Differential Regulation of Ghrelin and Nucleobindin 2 (NUCB2)/Nesfatin-1

2015 ◽  
Vol 29 (11) ◽  
pp. 1571-1580 ◽  
Author(s):  
Liangxiao Ma ◽  
Hong Tang ◽  
Yue Yin ◽  
Ruili Yu ◽  
Jing Zhao ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Differential Regulation ◽  
Chow Diet ◽  
High Fat ◽  
Subsequent Increase ◽  
Acetylation Site ◽  
Mtorc1 Signaling ◽  
Normal Chow

Abstract Sodium valporate (VPA), a broad-spectrum inhibitor of histone deacetylases (HDACs), increased ghrelin whereas decreased nesfatin-1 in mice fed normal chow diet or high-fat diet. Alterations in ghrelin and nucleobindin 2/nesfatin-1 were mediated by HDAC5 but not HDAC4. Activation of mTORC1 significantly attenuated the effect of VPA on ghrelin and nesfatin-1 levels. HDAC5 coimmunoprecipitated with raptor. Inhibition of HDAC5 by VPA, trichostatin A, or siHDAC5 markedly increased acetylation of raptor Lys840 and subsequent phosphorylation of raptor Ser792, resulting in suppression of mTORC1 signaling. A raptor mutant lacking the Lys840 acetylation site showed a decrement in phosphorylation of raptor Ser792 and subsequent increase in mTORC1 signaling. These alterations were associated with reciprocal changes in ghrelin and nucleobindin 2/nesfatin-1 expression. These findings reveal HDAC5-mTORC1 signaling as a novel mechanism in the differential regulation of gastric ghrelin and nesfatin-1.

scholarly journals High-fat diet-induced β-cell proliferation occurs prior to insulin resistance in C57Bl/6J male mice

2015 ◽  
Vol 308 (7) ◽  
pp. E573-E582 ◽  
Author(s):  
Rockann E. Mosser ◽  
Matthew F. Maulis ◽  
Valentine S. Moullé ◽  
Jennifer C. Dunn ◽  
Bethany A. Carboneau ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
High Fat Diet ◽  
Cell Mass ◽  
Chow Diet ◽  
High Fat ◽  
Β Cell ◽  
Peripheral Insulin Resistance ◽  
Insulin Tolerance

Both short- (1 wk) and long-term (2–12 mo) high-fat diet (HFD) studies reveal enhanced β-cell mass due to increased β-cell proliferation. β-Cell proliferation following HFD has been postulated to occur in response to insulin resistance; however, whether HFD can induce β-cell proliferation independent of insulin resistance has been controversial. To examine the kinetics of HFD-induced β-cell proliferation and its correlation with insulin resistance, we placed 8-wk-old male C57Bl/6J mice on HFD for different lengths of time and assayed the following: glucose tolerance, insulin secretion in response to glucose, insulin tolerance, β-cell mass, and β-cell proliferation. We found that β-cell proliferation was significantly increased after only 3 days of HFD feeding, weeks before an increase in β-cell mass or peripheral insulin resistance was detected. These results were confirmed by hyperinsulinemic euglycemic clamps and measurements of α-hydroxybutyrate, a plasma biomarker of insulin resistance in humans. An increase in expression of key islet-proliferative genes was found in isolated islets from 1-wk HFD-fed mice compared with chow diet (CD)-fed mice. These data indicate that short-term HFD feeding enhances β-cell proliferation before insulin resistance becomes apparent.

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