scholarly journals The depot-specific and essential roles of CBP/p300 in regulating adipose plasticity

2019 ◽  
Vol 240 (2) ◽  
pp. 257-269 ◽  
Author(s):  
Maria Namwanje ◽  
Longhua Liu ◽  
Michelle Chan ◽  
Nikki Aaron ◽  
Michael J Kraakman ◽  
...  
Keyword(s):  
Body Weight ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Knockout Mice ◽  
Metabolic Disorders ◽  
Physiological Effects ◽  
Double Knockout ◽  
Adipose Tissues ◽  
Diet Induced Obesity ◽  
Specific Deletion

Fat remodeling has been extensively explored through protein deacetylation, but not yet acetylation, as a viable therapeutic approach in the management of obesity and related metabolic disorders. Here, we investigated the functions of key acetyltransferases CBP/p300 in adipose remodeling and their physiological effects by generating adipose-specific deletion of CBP (Cbp-AKO), p300 (p300-AKO) and double-knockout (Cbp/p300-AKO) models. We demonstrated that Cbp-AKO exhibited marked brown remodeling of inguinal WAT (iWAT) but not epididymal WAT (eWAT) after cold exposure and that this pattern was exaggerated in diet-induced obesity (DIO). Despite this striking browning phenotype, loss of Cbp was insufficient to impact body weight or glucose tolerance. In contrast, ablation of p300 in adipose tissues had minimal effects on fat remodeling and adiposity. Surprisingly, double-knockout mice (Cbp/p300-AKO) developed severe lipodystrophy along with marked hepatic steatosis, hyperglycemia and hyperlipidemia. Furthermore, we demonstrated that pharmacological inhibition of Cbp and p300 activity suppressed adipogenesis. Collectively, these data suggest that (i) CBP, but not p300, has distinct functions in regulating fat remodeling and that this occurs in a depot-selective manner; (ii) brown remodeling occurs independently of the improvements in glucose metabolism and obesity and (iii) the combined roles of CBP and p300 are indispensable for normal adipose development.

scholarly journals The Effects of Erythropoietin Dose Titration during High-Fat Diet-Induced Obesity

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Amanda Foskett ◽  
Mawadda Alnaeeli ◽  
Li Wang ◽  
Ruifeng Teng ◽  
Constance T. Noguchi
Keyword(s):  
Physical Activity ◽  
Body Weight ◽  
Food Intake ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Fat Mass ◽  
High Fat Diet ◽  
Metabolic Effects ◽  
High Fat ◽  
Diet Induced Obesity

Erythropoietin (Epo) is a pleotropic cytokine with several nonhematopoietic tissue effects. High-dose Epo treatment-mediated effects on body weight, fat mass and glucose tolerance have recently been reported, thus extending its pleotropic effects to fat and glucose metabolism. However, the exact dose range of Epo treatment required for such effects remains unidentified to date. We investigated Epo dosage effect (up to 1000 U/kg) on hematocrit, body weight, body composition, glucose metabolism, food intake, and physical activity, during high-fat diet-induced obesity. We report that Epo doses (1000, 600, 300, and 150 U/kg) significantly reduced body weight gain and fat mass, while, only Epo doses of 300 U/kg and higher significantly affected glucose tolerance. None of the tested Epo doses showed any detectable effects on food intake, and only 1000 U/kg dose significantly increased physical activity, suggesting that these parameters may only be partially responsible for the metabolic effects of Epo treatment.

scholarly journals Effects of sleeve gastrectomy and ileal transposition, alone and in combination, on food intake, body weight, gut hormones, and glucose metabolism in rats

2013 ◽  
Vol 305 (4) ◽  
pp. E507-E518 ◽  
Author(s):  
S. Nausheen ◽  
I. H. Shah ◽  
A. Pezeshki ◽  
D. L. Sigalet ◽  
P. K. Chelikani
Keyword(s):  
Body Weight ◽  
Sleeve Gastrectomy ◽  
Weight Gain ◽  
Food Intake ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Gut Hormones ◽  
Ileal Transposition ◽  
Gastric Restriction ◽  
Peripheral Tissues

Bariatric surgeries are hypothesized to produce weight loss and improve diabetes control by multiple mechanisms including gastric restriction and lower gut stimulation; the relative importance of these mechanisms remains poorly understood. We compared the effects of a typical foregut procedure, sleeve gastrectomy, (SG) with a primarily hindgut surgery, ileal transposition (IT), alone and together (SGIT), or sham manipulations, on food intake, body weight, gut hormones, glucose tolerance, and key markers of glucose homeostasis in peripheral tissues of adult male Sprague-Dawley rats (450–550 g, n = 7–9/group). SG, IT, and SGIT surgeries produced transient reduction in food intake and weight gain; the effects of SG and IT on intake and body weight were nonadditive. SG, IT, and SGIT surgeries resulted in increased tissue expression and plasma concentrations of the lower gut hormones glucagon-like peptide-1 and peptide YY and decreased plasma glucose-dependent insulinotropic peptide, insulin, and leptin concentrations. Despite transient effects on intake and weight gain, the SG, IT, and SGIT surgeries produced a significant improvement in glucose tolerance. In support of glycemic improvements, the protein abundance of key markers of glucose metabolism (e.g., GLUT4, PKA, IRS-1) in muscle and adipose tissue were increased, whereas the expression of key gluconeogenic enzyme in liver (G-6-Pase) were decreased following the surgeries. Therefore, our data suggest that enhanced lower gut stimulation following SG, IT, and SGIT surgeries leads to transient reduction in food intake and weight gain together with enhanced secretion of lower gut hormones and improved glucose clearance by peripheral tissues.

scholarly journals A Defect in Interleukin-10 Leads to Enhanced Malarial Disease in Plasmodium chabaudi chabaudi Infection in Mice

1999 ◽  
Vol 67 (9) ◽  
pp. 4435-4442 ◽  
Author(s):  
Ching Li ◽  
Inés Corraliza ◽  
Jean Langhorne
Keyword(s):  
Body Weight ◽  
Knockout Mice ◽  
Interleukin 10 ◽  
Plasmodium Chabaudi ◽  
Double Knockout ◽  
Direct Stimulation ◽  
Necrosis Factor Alpha ◽  
Glucose Levels ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT Infection of interleukin-10 (IL-10)-nonexpressing (IL-10−/−) mice with Plasmodium chabaudi chabaudi (AS) leads to exacerbated pathology in female mice and death in a proportion of them. Hypoglycemia, hypothermia, and loss in body weight were significantly greater in female IL-10−/−mice than in male knockout mice and all wild-type (WT) mice during the acute phase of infection. At this time, both female and male IL-10−/− mice produced more gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and IL-12p40 mRNA than their respective WT counterparts. Inactivation of IFN-γ in IL-10−/− mice by the injection of anti-IFN-γ antibodies or by the generation of IL-10−/− IFN-γ receptor−/− double-knockout mice resulted in reduced mortality but did not affect body weight, temperature, or blood glucose levels. The data suggest that IFN-γ-independent pathways may be responsible for these pathological features of P. chabaudimalaria and may be due to direct stimulation of TNF-α by the parasite. Since male and female knockout mice both produce more inflammatory cytokines than their WT counterparts, it is likely that the mortality seen in females is due to the nature or magnitude of the response to these cytokines rather than the amount of IFN-γ or TNF-α produced.

scholarly journals Susceptibility to diet induced obesity at thermoneutral conditions is independent of UCP1

2021 ◽  
Author(s):  
Sebastian Dieckmann ◽  
Akim Strohmeyer ◽  
Monja Willershaeuser ◽  
Stefanie Maurer ◽  
Wolfgang Wurst ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Knockout Mice ◽  
Body Weight Gain ◽  
Uncoupling Protein ◽  
Exon 2 ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Knockout Model

Objective Activation of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) upon cold stimulation leads to substantial increase in energy expenditure to defend body temperature. Increases in energy expenditure after a high caloric food intake, termed diet-induced thermogenesis, are also attributed to BAT. These properties render BAT a potential target to combat diet-induced obesity. However, studies investigating the role of UCP1 to protect against diet-induced obesity are controversial and rely on the phenotyping of a single constitutive UCP1-knockout model. To address this issue, we generated a novel UCP1-knockout model by Cre-mediated deletion of Exon 2 in the UCP1 gene. We studied the effect of constitutive UCP1 knockout on metabolism and the development of diet-induced obesity. Methods UCP1 knockout and wildtype mice were housed at 30°C and fed a control diet for 4-weeks followed by 8-weeks of high-fat diet. Body weight and food intake were monitored continuously over the course of the study and indirect calorimetry was used to determine energy expenditure during both feeding periods. Results Based on Western blot analysis, thermal imaging and noradrenaline test, we confirmed the lack of functional UCP1 in knockout mice. However, body weight gain, food intake and energy expenditure were not affected by deletion of UCP1 gene function during both feeding periods. Conclusion Conclusively, we show that UCP1 does not protect against diet-induced obesity at thermoneutrality. Further we introduce a novel UCP1-KO mouse enabling the generation of conditional UCP1-knockout mice to scrutinize the contribution of UCP1 to energy metabolism in different cell types or life stages.

scholarly journals Tpcn2 knockout mice have improved insulin sensitivity and are protected against high-fat diet-induced weight gain

2018 ◽  
Vol 50 (8) ◽  
pp. 605-614
Author(s):  
Hong He ◽  
Katie Holl ◽  
Sarah DeBehnke ◽  
Chay Teng Yeo ◽  
Polly Hansen ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Male And Female ◽  
Female Mice

Type 2 diabetes is a complex disorder affected by multiple genes and the environment. Our laboratory has shown that in response to a glucose challenge, two-pore channel 2 ( Tpcn2) knockout mice exhibit a decreased insulin response but normal glucose clearance, suggesting they have improved insulin sensitivity compared with wild-type mice. We tested the hypothesis that improved insulin sensitivity in Tpcn2 knockout mice would protect against the negative effects of a high fat diet. Male and female Tpcn2 knockout (KO), heterozygous (Het), and wild-type (WT) mice were fed a low-fat (LF) or high-fat (HF) diet for 24 wk. HF diet significantly increases body weight in WT mice relative to those on the LF diet; this HF diet-induced increase in body weight is blunted in the Het and KO mice. Despite the protection against diet-induced weight gain, however, Tpcn2 KO mice are not protected against HF-diet-induced changes in glucose or insulin area under the curve during glucose tolerance tests in female mice, while HF diet has no significant effect on glucose tolerance in the male mice, regardless of genotype. Glucose disappearance during an insulin tolerance test is augmented in male KO mice, consistent with our previous findings suggesting enhanced insulin sensitivity in these mice. Male KO mice exhibit increased fasting plasma total cholesterol and triglyceride concentrations relative to WT mice on the LF diet, but this difference disappears in HF diet-fed mice where there is increased cholesterol and triglycerides across all genotypes. These data demonstrate that knockout of Tpcn2 may increase insulin action in male, but not female, mice. In addition, both male and female KO mice are protected against diet-induced weight gain, but this protection is likely independent from glucose tolerance, insulin sensitivity, and plasma lipid levels.

scholarly journals Deficiency of lymphotoxin-α does not exacerbate high-fat diet-induced obesity but does enhance inflammation in mice

2012 ◽  
Vol 302 (8) ◽  
pp. E961-E971 ◽  
Author(s):  
Nathalie Pamir ◽  
Timothy S. McMillen ◽  
Kimberly A. Edgel ◽  
Francis Kim ◽  
Renée C. LeBoeuf
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Tissue Level ◽  
Specific Gene ◽  
High Fat ◽  
Tissue Macrophage ◽  
Diet Induced Obesity ◽  
Inflammatory Status ◽  
Lymphotoxin Α

Lymphotoxin-α (LTα) is secreted by lymphocytes and acts through tumor necrosis factor-α receptors and the LTβ receptor. Our goals were to determine whether LT has a role in obesity and investigate whether LT contributes to the link between obesity and adipose tissue lymphocyte accumulation. LT deficient (LT−/−) and wild-type (WT) mice were fed standard pelleted rodent chow or a high-fat/high-sucrose diet (HFHS) for 13 wk. Body weight, body composition, and food intake were measured. Glucose tolerance was assessed. Systemic and adipose tissue inflammatory statuses were evaluated by quantifying plasma adipokine levels and tissue macrophage and T cell-specific gene expression in abdominal fat. LT−/− mice were smaller (20%) and leaner (25%) than WT controls after 13 wk of HFHS diet feeding. LT−/− mice showed improved glucose tolerance, suggesting that, in WT mice, LT may impair glucose metabolism. Surprisingly, adipose tissue from rodent chow- and HFHS-fed LT−/− mice exhibited increased T lymphocyte and macrophage infiltration compared with WT mice. Despite the fact that LT−/− mice exhibited an enhanced inflammatory status at the systemic and tissue level even when fed rodent chow, they were protected from enhanced diet-induced obesity and insulin resistance. Thus, LT contributes to body weight and adiposity and is required to modulate the accumulation of immune cells in adipose tissue.

Diet-induced obesity and pancreatic islet blood flow in the rat: a preferential increase in islet blood perfusion persists after withdrawal of the diet and normalization of body weight

1996 ◽  
Vol 151 (3) ◽  
pp. 507-511 ◽  
Author(s):  
A M Svensson ◽  
C Hellerström ◽  
L Jansson
Keyword(s):  
Blood Flow ◽  
Body Weight ◽  
Glucose Tolerance ◽  
Pancreatic Islet ◽  
Wistar Rats ◽  
Blood Perfusion ◽  
Cafeteria Diet ◽  
Standard Diet ◽  
Diet Induced Obesity ◽  
Islet Blood Flow

Abstract The aim of the present study was to evaluate the effects of diet-induced obesity on pancreatic islet blood perfusion in normal Wistar rats. Furthermore, we investigated to what extent any obesity-associated changes in islet blood flow could be reversed after reversion to a normal diet with normalization of body weight. Young adult female Wistar rats were offered a palatable mixed high-caloric diet (cafeteria diet) in addition to standard pelleted chow. Age-matched control rats received standard pelleted chow only. After 4 weeks the diet-treated rats had a body weight of approximately 15% more than that of the controls. All diet-treated rats had decreased glucose tolerance and increased serum insulin concentrations, but basal blood glucose concentrations were similar in anesthetized diet-treated and control rats. Whole pancreatic and islet blood flow rates were measured with a microsphere technique. The islet blood flow as well as fractional islet blood flow were increased (P<0·01) in rats fed the cafeteria diet, while blood perfusion of the whole pancreas was similar to that of the control rats. In a second experiment, rats received the cafeteria diet for 4 weeks and were then fed standard pelleted food alone for another 3 weeks, while controls received standard diet for 7 weeks. After this period total body weight, retroperitoneal fat pad weight and glucose tolerance were similar to those of the controls. Whole pancreatic blood flow was unchanged as compared with that of control rats. However, both islet blood flow (P<0·01) and fractional blood flow (P<0·01) were increased. We conclude that diet-induced obesity in rats is associated with decreased glucose tolerance, hyperinsulinemia and a specific increase in absolute and fractional islet blood perfusion. This increase persists for at least 3 weeks after the diet is withdrawn despite normalization of body weight and glucose tolerance. Journal of Endocrinology (1996) 151, 507–511

scholarly journals Chronic dietary erythritol exposure elevates fasting plasma erythritol levels but does not cause weight gain or modify glucose homeostasis in mice

2021 ◽  
Author(s):  
Semira R. Ortiz ◽  
Martha S. Field
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Uncoupling Protein ◽  
Disease Onset ◽  
Cardiometabolic Disease ◽  
Brown Adipose ◽  
Ucp1 Expression ◽  
Old Mice

AbstractObjectiveErythritol is both a common non-nutritive sweetener (NNS) and an endogenous product of glucose metabolism. Recent reports indicate that elevated plasma erythritol is a predictive biomarker of cardiometabolic disease onset and complications. Although short-term erythritol consumption has been evaluated, the effect of chronically elevated circulating erythritol on adiposity and glucose metabolism has not. This study investigated the effect of longer-term erythritol consumption on weight gain and glucose tolerance, and the interaction between dietary composition and erythritol supplementation on these parameters.Methods8-week-old and 20-week-old C57BL/6J mice were randomized to consume low-fat diet (LFD), high-fat diet (HFD), LFD with 40g/kg erythritol (LFD+ERY), and HFD with 40g/kg erythritol (HFD+ERY) groups. After 8 weeks, plasma erythritol, body weight and composition, food intake, glucose tolerance, and brown adipose tissue (BAT) uncoupling protein 1 (UCP1) expression were measured.ResultsPlasma erythritol was elevated 40-fold in mice consuming LFD+ERY or HFD+ERY relative to mice consuming LFD or HFD, respectively. Liver and kidney tissue contained higher levels of erythritol than adipose. Unexpectedly, there was no effect of erythritol supplementation on body weight or glucose tolerance in 8- or 20-week-old mice fed LFD+ERY, or in 8-week-old mice fed HFD+ERY. In 20-week-old mice fed HFD+ERY, there was a significant interaction between erythritol and body weight (p<0.0001) compared to controls, but the main effect of diet was not significant. We also found no effect of chronic erythritol consumption on BAT UCP1 expression.ConclusionProlonged erythritol consumption did not significantly impact body weight, composition, or glucose tolerance. This suggests that dietary erythritol does not contribute to the development of cardiometabolic disease.

scholarly journals Disruption of Phospholipid Transfer Protein–Mediated High-Density Lipoprotein Maturation Reduces Scavenger Receptor BI Deficiency–Driven Atherosclerosis Susceptibility Despite Unexpected Metabolic Complications

2020 ◽  
Vol 40 (3) ◽  
pp. 611-623 ◽  
Author(s):  
Menno Hoekstra ◽  
Ronald J. van der Sluis ◽  
Reeni B. Hildebrand ◽  
Bart Lammers ◽  
Ying Zhao ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Knockout Mice ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Phospholipid Transfer Protein ◽  
Double Knockout ◽  
Metabolic Complications ◽  
Scavenger Receptor Bi ◽  
Transfer Protein ◽  
Phospholipid Transfer

Objective: We tested the hypothesis that enlarged, dysfunctional HDL (high-density lipoprotein) particles contribute to the augmented atherosclerosis susceptibility associated with SR-BI (scavenger receptor BI) deficiency in mice. Approach and Results: We eliminated the ability of HDL particles to fully mature by targeting PLTP (phospholipid transfer protein) functionality. Particle size of the HDL population was almost fully normalized in male and female SR-BI×PLTP double knockout mice. In contrast, the plasma unesterified cholesterol to cholesteryl ester ratio remained elevated. The PLTP deficiency-induced reduction in HDL size in SR-BI knockout mice resulted in a normalized aortic tissue oxidative stress status on Western-type diet. Atherosclerosis susceptibility was—however—only partially reversed in double knockout mice, which can likely be attributed to the fact that they developed a metabolic syndrome-like phenotype characterized by obesity, hypertriglyceridemia, and a reduced glucose tolerance. Mechanistic studies in chow diet–fed mice revealed that the diminished glucose tolerance was probably secondary to the exaggerated postprandial triglyceride response. The absence of PLTP did not affect LPL (lipoprotein lipase)-mediated triglyceride lipolysis but rather modified the ability of VLDL (very low-density lipoprotein)/chylomicron remnants to be cleared from the circulation by the liver through receptors other than SR-BI. As a result, livers of double knockout mice only cleared 26% of the fractional dose of [ 14 C]cholesteryl oleate after intravenous VLDL-like particle injection. Conclusions: We have shown that disruption of PLTP-mediated HDL maturation reduces SR-BI deficiency-driven atherosclerosis susceptibility in mice despite the induction of proatherogenic metabolic complications in the double knockout mice.

Abstract 468: The Dopamine D 1 -like Receptors Negatively Regulate the Expression and Function of the a 1 A Adrenergic Receptor

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Riley C Ennis ◽  
Van Anthony M Villar ◽  
Laureano D Asico ◽  
Crisanto S Escano ◽  
Jun B Feranil ◽  
...  
Keyword(s):  
Body Weight ◽  
Plasma Membrane ◽  
Knockout Mice ◽  
Adrenergic Receptor ◽  
Human Kidney ◽  
Proximal Tubules ◽  
Mouse Strains ◽  
Double Knockout ◽  
R And D ◽  
And Function

The homeostatic control of blood pressure hinges upon the delicate balance between pro-hypertensinogenic (e.g., sympathetic nervous system) and anti-hypertensinogenic systems (e.g., dopamine system). The D 1 -like dopamine receptors (D 1 R and D 5 R) and the α 1A adrenergic receptor (ARα 1A ) are endogenously expressed in the renal proximal tubules and engender opposing effects on sodium transport, i.e., natriuresis (D 1 R and D 5 R) or anti-natriuresis (ARα 1A ). We tested the hypothesis that the D 1 R and D 5 R interact with and regulate the ARα 1A in human renal proximal tubule cells (hRPTCs) and in mice. We found that the D 1 R and D 5 R colocalized with the ARα 1A in hRPTCs and in proximal tubules in human kidney sections. Both receptors immunoprecipitated, pulled-down, and co-fractionated with ARα 1A in lipid rafts. Short-term co-treatment with fenoldopam (1 μM, 15 min) reversed the ARα 1 agonist phenylephrine (10 μM, 15 min)-induced Na + ,K + -ATPase (NKA) translocation from the cytosol to the plasma membrane in hRPTCs (plasma membrane NKA: vehicle=100±5% vs. fenoldopam=65±3% vs. phenylephrine=177±5% vs. co-treatment=115±7%; P<0.05, n=3-4). Long-term fenoldopam (1 μM, 24 hr) treatment resulted in decreased D 1 R (70.0±5.9%, P<0.05, n=3) and D 5 R (50.1±10.7%, P<0.05, n=3), consistent with D 1 -like receptor desensitization, but increased ARα 1A abundance (142.6±4.3%, P<0.05, n=3) in hRPTCs. RNAi silencing of ARα 1A (48 hr) increased the expression of D 1 R and D 5 R. To determine the extent of regulation of each D 1 -like receptor on ARα 1A , we used the subclass-selective ARα 1 agonist phenylephrine (5 μg/kg body weight, i.p.) and the receptor-specific ARα 1A agonist A610603 (25 ng/kg body weight, i.p.) to inhibit Na + excretion in three mouse strains. Phenylephrine treatment resulted in 59.6%, 84.2%, 99.3%, and 99.5% reduction from basal level of 24-hr Na + excretion_while A61603 treatment resulted in 42.4%, 67.1%, 99.9%, and 100% reduction_in wild-type controls, D 1 R -/- , and D 5 R -/- knockout mice, and D 1 R/D 5 R -/- double knockout mice, respectively, suggesting a stronger regulatory effect of D 5 R on ARα 1A . Elucidating the intricacies of the interaction among these receptors is crucial for a better understanding of the crosstalk between anti- and pro-hypertensive systems.

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