Hepatocyte Retinoid X Receptor-α-Deficient Mice Have Reduced Food Intake, Increased Body Weight, and Improved Glucose Tolerance

Hepatocyte retinoid X receptor (RXR)α-deficient mice and wild-type mice were fed either a regular or a high-saturated-fat diet for 12 wk to study the functional role of hepatocyte RXRα in fatty acid and carbohydrate metabolism. Food intake was significantly reduced in hepatocyte RXRα-deficient mice when either diet was used. The amount of food intake was negatively associated with serum leptin level. Although mutant mice ate less, body weight and fat content were significantly higher in mutant than wild-type mice. Examination of the expression of peroxisome proliferator-activated receptor-α target genes indicated that the peroxisome proliferator-activated receptor-α-mediated pathway was compromised in the mutant mice, which, in turn, might affect fatty-acid metabolism and result in increased body weight and fat content. Although mutant mice were obese, they demonstrated the same degree of insulin sensitivity and the same level of serum insulin as the wild-type mice. However, these mutant mice have improved glucose tolerance. To explore a mechanism that may be responsible for the improved glucose tolerance, serum IGF-I level was examined. Serum IGF-1 level was significantly increased in mutant mice compared with wild-type mice. Taken together, hepatocyte RXRα deficiency increases leptin level and reduces food intake. Those mice also develop obesity, with an unexpected improvement of glucose tolerance. The result also suggests that an increase in serum IGF-I level might be one of the mechanisms leading to improved glucose tolerance in hepatocyte RXRα-deficient mice.

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Cevoglitazar, a Novel Peroxisome Proliferator-Activated Receptor-α/γ Dual Agonist, Potently Reduces Food Intake and Body Weight in Obese Mice and Cynomolgus Monkeys

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.95.6.9992 ◽

2010 ◽

Vol 95 (6) ◽

pp. 3076-3076

Author(s):

Hong Chen ◽

Beatriz Dardik ◽

Ling Qiu ◽

Xianglin Ren ◽

Shari L. Caplan ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Peroxisome Proliferator ◽

Obese Mice ◽

Peroxisome Proliferator Activated Receptor ◽

Cynomolgus Monkeys ◽

Dual Agonist

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Cyanidin-3-O-Galactoside-Enriched Aronia melanocarpa Extract Attenuates Weight Gain and Adipogenic Pathways in High-Fat Diet-Induced Obese C57BL/6 Mice

Nutrients ◽

10.3390/nu11051190 ◽

2019 ◽

Vol 11 (5) ◽

pp. 1190 ◽

Cited By ~ 9

Author(s):

Su-Min Lim ◽

Hyun Sook Lee ◽

Jae In Jung ◽

So Mi Kim ◽

Nam Young Kim ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Food Intake ◽

High Fat Diet ◽

Fatty Acid Synthase ◽

Binding Protein ◽

Peroxisome Proliferator ◽

High Fat ◽

Peroxisome Proliferator Activated Receptor ◽

Aronia Melanocarpa

Aronia melanocarpa are a rich source of anthocyanins that have received considerable interest for their relations to human health. In this study, the anti-adipogenic effect of cyanidin-3-O-galactoside-enriched Aronia melanocarpa extract (AM-Ex) and its underlying mechanisms were investigated in an in vivo system. Five-week-old male C57BL/6N mice were randomly divided into five groups for 8-week feeding with a control diet (CD), a high-fat diet (HFD), or a HFD with 50 (AM-Ex 50), 100 (AM-Ex 100), or 200 AM-Ex (AM-Ex 200) mg/kg body weight/day. HFD-fed mice showed a significant increase in body weight compared to the CD group, and AM-Ex dose-dependently inhibited this weight gain. AM-Ex significantly reduced the food intake and the weight of white fat tissue, including epididymal fat, retroperitoneal fat, mesenteric fat, and inguinal fat. Treatment with AM-Ex (50 to 200 mg/kg) reduced serum levels of leptin, insulin, triglyceride, total cholesterol, and low density lipoprotein (LDL)-cholesterol. Real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that AM-Ex suppressed adipogenesis by decreasing CCAAT/enhancer binding protein α, peroxisome proliferator-activated receptor γ, sterol regulatory element-binding protein-1c, peroxisome proliferator-activated receptor gamma coactivator-1α, acetyl-CoA carboxylase 1, ATP-citrate lyase, fatty acid synthase, and adipocyte protein 2 messenger RNA (mRNA) expressions. These results suggest that AM-Ex is potentially beneficial for the suppression of HFD-induced obesity by modulating multiple pathways associated with adipogenesis and food intake.

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Deficiency of FcϵR1 Increases Body Weight Gain but Improves Glucose Tolerance in Diet-Induced Obese Mice

Endocrinology ◽

10.1210/en.2015-1184 ◽

2015 ◽

Vol 156 (11) ◽

pp. 4047-4058 ◽

Cited By ~ 2

Author(s):

Yun-Jung Lee ◽

Conglin Liu ◽

Mengyang Liao ◽

Galina K. Sukhova ◽

Jun Shirakawa ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Insulin Secretion ◽

Weight Gain ◽

Glucose Tolerance ◽

Glucose Uptake ◽

Body Weight Gain ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Enhancer Binding Protein

Prior studies demonstrated increased plasma IgE in diabetic patients, but the direct participation of IgE in diabetes or obesity remains unknown. This study found that plasma IgE levels correlated inversely with body weight, body mass index, and body fat mass among a population of randomly selected obese women. IgE receptor FcϵR1-deficient (Fcer1a−/−) mice and diet-induced obesity (DIO) mice demonstrated that FcϵR1 deficiency in DIO mice increased food intake, reduced energy expenditure, and increased body weight gain but improved glucose tolerance and glucose-induced insulin secretion. White adipose tissue from Fcer1a−/− mice showed an increased expression of phospho-AKT, CCAAT/enhancer binding protein-α, peroxisome proliferator-activated receptor-γ, glucose transporter-4 (Glut4), and B-cell lymphoma 2 (Bcl2) but reduced uncoupling protein 1 (UCP1) and phosphorylated c-Jun N-terminal kinase (JNK) expression, tissue macrophage accumulation, and apoptosis, suggesting that IgE reduces adipogenesis and glucose uptake but induces energy expenditure, adipocyte apoptosis, and white adipose tissue inflammation. In 3T3-L1 cells, IgE inhibited the expression of CCAAT/enhancer binding protein-α and peroxisome proliferator-activated receptor-γ, and preadipocyte adipogenesis and induced adipocyte apoptosis. IgE reduced the 3T3-L1 cell expression of Glut4, phospho-AKT, and glucose uptake, which concurred with improved glucose tolerance in Fcer1a−/− mice. This study established two novel pathways of IgE in reducing body weight gain in DIO mice by suppressing adipogenesis and inducing adipocyte apoptosis while worsening glucose tolerance by reducing Glut4 expression, glucose uptake, and insulin secretion.

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Cevoglitazar, a Novel Peroxisome Proliferator-Activated Receptor-α/γ Dual Agonist, Potently Reduces Food Intake and Body Weight in Obese Mice and Cynomolgus Monkeys

Endocrine Reviews ◽

10.1210/edrv.31.3.9995 ◽

2010 ◽

Vol 31 (3) ◽

pp. 404-405

Author(s):

Hong Chen ◽

Beatriz Dardik ◽

Ling Qiu ◽

Xianglin Ren ◽

Shari L. Caplan ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Plasma Levels ◽

Energy Homeostasis ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Cynomolgus Monkeys ◽

Dose Dependent ◽

Dual Agonist

ABSTRACT Cevoglitazar is a dual agonist for the peroxisome proliferator-activated receptor (PPAR)-α and -γ subtypes. Dual activation of PPARα and -γ is a therapeutic approach in development for the treatment of type 2 diabetes mellitus and diabetic dyslipidemia. In this report, we show that, in addition to improving insulin sensitivity and lipid metabolism like other dual PPAR agonists, cevoglitazar also elicits beneficial effects on energy homeostasis in two animal models of obesity. In leptin-deficient ob/ob mice, administration of cevoglitazar at 0.5, 1, or 2 mg/kg for 18 d led to acute and sustained, dose-dependent reduction of food intake and body weight. Furthermore, plasma levels of glucose and insulin were normalized after 7 d of cevoglitazar treatment at 0.5 mg/kg. Plasma levels of free fatty acids and triglycerides were dose-dependently reduced. In obese and insulin-resistant cynomolgus monkeys, treatment with cevoglitazar at 50 and 500 μg/kg for 4 wk lowered food intake and body weight in a dose-dependent manner. In these animals, cevoglitazar also reduced fasting plasma insulin and, at the highest dose, reduced hemoglobin A1c levels by 0.4%. These preclinical results demonstrate that cevoglitazar holds promise for the treatment of diabetes and obesity-related disorders because of its unique beneficial effect on energy balance in addition to improving glycemic and metabolic control.

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Altered Growth in Male Peroxisome Proliferator-Activated Receptor γ (PPARγ) Heterozygous Mice: Involvement of PPARγ in a Negative Feedback Regulation of Growth Hormone Action

Molecular Endocrinology ◽

10.1210/me.2003-0325 ◽

2004 ◽

Vol 18 (10) ◽

pp. 2363-2377 ◽

Cited By ~ 30

Author(s):

Jennifer Rieusset ◽

Josiane Seydoux ◽

Silvia I. Anghel ◽

Pascal Escher ◽

Liliane Michalik ◽

...

Keyword(s):

Body Size ◽

Negative Regulator ◽

Mutant Mice ◽

Cytokine Signaling ◽

Peroxisome Proliferator ◽

Gene Encoding ◽

Negative Feedback Regulation ◽

Peroxisome Proliferator Activated Receptor ◽

Reduced Body ◽

Igf I

Abstract The peroxisome proliferator-activated receptor γ (PPARγ) plays a major role in fat tissue development and physiology. Mutations in the gene encoding this receptor have been associated to disorders in lipid metabolism. A thorough investigation of mice in which one PPARγ allele has been mutated reveals that male PPARγ heterozygous (PPARγ +/−) mice exhibit a reduced body size associated with decreased body weight, reflecting lean mass reduction. This phenotype is reproduced when treating the mice with a PPARγ- specific antagonist. Monosodium glutamate treatment, which induces weight gain and alters body growth in wild-type mice, further aggravates the growth defect of PPARγ +/− mice. The levels of circulating GH and that of its downstream effector, IGF-I, are not altered in mutant mice. However, the IGF-I mRNA level is decreased in white adipose tissue (WAT) of PPARγ +/− mice and is not changed by acute administration of recombinant human GH, suggesting an altered GH action in the mutant animals. Importantly, expression of the gene encoding the suppressor of cytokine signaling-2, which is an essential negative regulator of GH signaling, is strongly increased in the WAT of PPARγ +/− mice. Although the relationship between the altered GH signaling in WAT and reduced body size remains unclear, our results suggest a novel role of PPARγ in GH signaling, which might contribute to the metabolic disorder affecting insulin signaling in PPARγ mutant mice.

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Mice with chronically increased circulating ghrelin develop age-related glucose intolerance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00463.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. E752-E760 ◽

Cited By ~ 30

Author(s):

Jacquelyn A. Reed ◽

Stephen C. Benoit ◽

Paul T. Pfluger ◽

Matthias H. Tschöp ◽

David A. D'Alessio ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Glucose Tolerance ◽

Glucose Intolerance ◽

Fat Mass ◽

Neuron Specific Enolase ◽

Normal Glucose Tolerance ◽

Mrna Levels ◽

Wild Type ◽

Age Related

Ghrelin is a gut peptide that stimulates food intake and increases body fat mass when administered centrally or peripherally. In this study, ghrelin was overexpressed in neurons using the neuron-specific enolase (NSE) promoter sequences and mouse ghrelin cDNA (NSE-Ghr). Ghrelin expression in NSE-Ghr brain tissues was increased compared with wild-type mice. Ghrelin expression was also increased to a much smaller extent in liver of these mice, but mRNA levels in stomach or duodenum did not differ from wild-type mice. Body weight and composition was analyzed in two lines of NSE-Ghr mice, one line with increased circulating bioactive ghrelin (L43) and one line without (L73). No increases in body weight, food intake, or fat mass were found. Energy expenditure was measured in L43 mice and did not differ from wild-type controls, whereas locomotor activity was increased in NSE-Ghr mice. Young NSE-Ghr mice had normal glucose tolerance; however, L43 NSE-Ghr mice, but not L73 mice, developed glucose intolerance at 32 wk of age. Despite the impaired glucose tolerance in L43 mice, insulin levels did not differ from those of wild-type mice. These findings suggest a role for ghrelin in age-associated impairments of glucose homeostasis.

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Cevoglitazar, a Novel Peroxisome Proliferator-Activated Receptor-α/γ Dual Agonist, Potently Reduces Food Intake and Body Weight in Obese Mice and Cynomolgus Monkeys

Endocrinology ◽

10.1210/en.2009-1366 ◽

2010 ◽

Vol 151 (7) ◽

pp. 3115-3124 ◽

Cited By ~ 18

Author(s):

Hong Chen ◽

Beatriz Dardik ◽

Ling Qiu ◽

Xianglin Ren ◽

Shari L. Caplan ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Plasma Levels ◽

Energy Homeostasis ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Cynomolgus Monkeys ◽

Dose Dependent ◽

Dual Agonist

Cevoglitazar is a dual agonist for the peroxisome proliferator-activated receptor (PPAR)-α and -γ subtypes. Dual activation of PPARα and -γ is a therapeutic approach in development for the treatment of type 2 diabetes mellitus and diabetic dyslipidemia. In this report, we show that, in addition to improving insulin sensitivity and lipid metabolism like other dual PPAR agonists, cevoglitazar also elicits beneficial effects on energy homeostasis in two animal models of obesity. In leptin-deficient ob/ob mice, administration of cevoglitazar at 0.5, 1, or 2 mg/kg for 18 d led to acute and sustained, dose-dependent reduction of food intake and body weight. Furthermore, plasma levels of glucose and insulin were normalized after 7 d of cevoglitazar treatment at 0.5 mg/kg. Plasma levels of free fatty acids and triglycerides were dose-dependently reduced. In obese and insulin-resistant cynomolgus monkeys, treatment with cevoglitazar at 50 and 500 μg/kg for 4 wk lowered food intake and body weight in a dose-dependent manner. In these animals, cevoglitazar also reduced fasting plasma insulin and, at the highest dose, reduced hemoglobin A1c levels by 0.4%. These preclinical results demonstrate that cevoglitazar holds promise for the treatment of diabetes and obesity-related disorders because of its unique beneficial effect on energy balance in addition to improving glycemic and metabolic control.

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Acyloxyacyl hydrolase regulates voiding activity

AJP Renal Physiology ◽

10.1152/ajprenal.00442.2019 ◽

2020 ◽

Vol 318 (4) ◽

pp. F1006-F1016 ◽

Cited By ~ 1

Author(s):

Lizath M. Aguiniga ◽

Timothy J. Searl ◽

Afrida Rahman-Enyart ◽

Ryan E. Yaggie ◽

Wenbin Yang ◽

...

Keyword(s):

Brain Area ◽

Neuronal Firing ◽

Conditional Knockout ◽

Bladder Function ◽

Peroxisome Proliferator ◽

Wild Type ◽

Peroxisome Proliferator Activated Receptor ◽

Void Volumes ◽

Acyloxyacyl Hydrolase ◽

Deficient Mice

Corticotropin-releasing factor (CRF) regulates diverse physiological functions, including bladder control. We recently reported that Crf expression is under genetic control of Aoah, the locus encoding acyloxyacyl hydrolase (AOAH), suggesting that AOAH may also modulate voiding. Here, we examined the role of AOAH in bladder function. AOAH-deficient mice exhibited enlarged bladders relative to wild-type mice and had decreased voiding frequency and increased void volumes. AOAH-deficient mice had increased nonvoiding contractions and increased peak voiding pressure in awake cystometry. AOAH-deficient mice also exhibited increased bladder permeability and higher neuronal firing rates of bladder afferents in response to stretch. In wild-type mice, AOAH was expressed in bladder projecting neurons and colocalized in CRF-expressing neurons in Barrington’s nucleus, an important brain area for voiding behavior, and Crf was elevated in Barrington’s nucleus of AOAH-deficient mice. We had previously identified aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor-γ as transcriptional regulators of Crf, and conditional knockout of AhR or peroxisome proliferator-activated receptor-γ in Crf-expressing cells restored normal voiding in AOAH-deficient mice. Finally, an AhR antagonist improved voiding in AOAH-deficient mice. Together, these data demonstrate that AOAH regulates bladder function and that the AOAH- Crf axis is a therapeutic target for treating voiding dysfunction.

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Enterostatin decreases postprandial pancreatic UCP2 mRNA levels and increases plasma insulin and amylin

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00367.2004 ◽

2005 ◽

Vol 289 (1) ◽

pp. E40-E45 ◽

Cited By ~ 8

Author(s):

Denis Arsenijevic ◽

Eva Gallmann ◽

William Moses ◽

Thomas Lutz ◽

Charlotte Erlanson-Albertsson ◽

...

Keyword(s):

Body Weight ◽

Lipid Metabolism ◽

Food Intake ◽

Food Access ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Postprandial Metabolism ◽

Peroxisome Proliferator Activated Receptor ◽

Epididymal Fat

This study investigated the chronic effect of enterostatin on body weight and some of the associated changes in postprandial metabolism. Rats were adapted to 6 h of food access/day and a choice of low-fat and high-fat (HF) food and then given enterostatin or vehicle by an intraperitoneally implanted minipump delivering 160 nmol enterostatin/h continuously over a 5-day infusion period. Enterostatin resulted in a slight but significant reduction of HF intake and body weight. After the last 6-h food access period, enterostatin-treated animals had lower plasma triglyceride and free fatty acid but higher plasma glucose and lactate levels than control animals. Enterostatin infusion resulted in increased uncoupling protein-2 (UCP2) expression in various tissues, including epididymal fat and liver. UCP2 was reduced in the pancreas of enterostatin-treated animals, and this was associated with increased plasma levels of insulin and amylin. Whether these two hormones are involved in the observed decreased food intake due to enterostatin remains to be determined. As lipid metabolism appeared to be altered by enterostatin, we measured peroxisome proliferator-activated receptor (PPAR) expression in tissues and observed that PPARα, -β, -γ1, and -γ2 expression were modified by enterostatin in epididymal fat, pancreas, and liver. This further links altered lipid metabolism with body weight loss. Our data suggest that alterations in UCP2 and PPARγ2 play a role in the control of insulin and amylin release from the pancreas. This implies that enterostatin changes lipid and carbohydrate metabolic pathways in addition to its effects on food intake and energy expenditure.

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