scholarly journals High fat-fed GPR55 null mice display impaired glucose tolerance without concomitant changes in energy balance or insulin sensitivity but are less responsive to the effects of the cannabinoids rimonabant or Δ(9)-tetrahydrocannabivarin on weight gain

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9811
Author(s):  
Edward T. Wargent ◽  
Malgorzata Kepczynska ◽  
Mohamed Sghaier Zaibi ◽  
David C. Hislop ◽  
Jonathan R.S. Arch ◽  
...  
Keyword(s):  
Body Composition ◽  
Body Weight ◽  
Weight Gain ◽  
Energy Balance ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Insulin Tolerance

Background The insulin-sensitizing phytocannabinoid, Δ(9)-tetrahydrocannabivarin (THCV) can signal partly via G-protein coupled receptor-55 (GPR55 behaving as either an agonist or an antagonist depending on the assay). The cannabinoid receptor type 1 (CB1R) inverse agonist rimonabant is also a GPR55 agonist under some conditions. Previous studies have shown varied effects of deletion of GPR55 on energy balance and glucose homeostasis in mice. The contribution of signalling via GPR55 to the metabolic effects of THCV and rimonabant has been little studied. Methods In a preliminary experiment, energy balance and glucose homeostasis were studied in GPR55 knockout and wild-type mice fed on both standard chow (to 20 weeks of age) and high fat diets (from 6 to 15 weeks of age). In the main experiment, all mice were fed on the high fat diet (from 6 to 14 weeks of age). In addition to replicating the preliminary experiment, the effects of once daily administration of THCV (15 mg kg−1 po) and rimonabant (10 mg kg−1 po) were compared in the two genotypes. Results There was no effect of genotype on absolute body weight or weight gain, body composition measured by either dual-energy X-ray absorptiometry or Nuclear Magnetic Resonance (NMR), fat pad weights, food intake, energy expenditure, locomotor activity, glucose tolerance or insulin tolerance in mice fed on chow. When the mice were fed a high fat diet, there was again no effect of genotype on these various aspects of energy balance. However, in both experiments, glucose tolerance was worse in the knockout than the wild-type mice. Genotype did not affect insulin tolerance in either experiment. Weight loss in rimonabant- and THCV-treated mice was lower in knockout than in wild-type mice, but surprisingly there was no detectable effect of genotype on the effects of the drugs on any aspect of glucose homeostasis after taking into account the effect of genotype in vehicle-treated mice. Conclusions Our two experiments differ from those reported by others in finding impaired glucose tolerance in GPR55 knockout mice in the absence of any effect on body weight, body composition, locomotor activity or energy expenditure. Nor could we detect any effect of genotype on insulin tolerance, so the possibility that GPR55 regulates glucose-stimulated insulin secretion merits further investigation. By contrast with the genotype effect in untreated mice, we found that THCV and rimonabant reduced weight gain, and this effect was in part mediated by GPR55.

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 Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance

2016 ◽  
Vol 48 (7) ◽  
pp. 491-501 ◽  
Author(s):  
Madeliene Stump ◽  
Deng-Fu Guo ◽  
Ko-Ting Lu ◽  
Masashi Mukohda ◽  
Xuebo Liu ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Energy Balance ◽  
High Fat Diet ◽  
Control Diet ◽  
Cre Recombinase ◽  
Dominant Negative ◽  
High Fat ◽  
Pparγ Agonist ◽  
The Brain

Peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPARγ in mouse brain, and specifically in the pro-opiomelanocortin (POMC) neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPARγ in POMC neurons controls energy balance, we constructed a Cre-recombinase-dependent conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ and the tdTomato reporter. Inducible expression of both forms of PPARγ was validated in cells in culture, in liver of mice infected with an adenovirus expressing Cre-recombinase (AdCre), and in the brain of mice expressing Cre-recombinase either in all neurons (NESCre/PPARγ-P467L) or selectively in POMC neurons (POMCCre/PPARγ-P467L). Whereas POMCCre/PPARγ-P467L mice exhibited a normal pattern of weight gain when fed 60% high-fat diet, they exhibited increased weight gain and fat mass accumulation in response to a 10% fat isocaloric-matched control diet. POMCCre/PPARγ-P467L mice were leptin sensitive on control diet but became leptin resistant when fed 60% high-fat diet. There was no difference in body weight between POMCCre/PPARγ-WT mice and controls in response to 60% high-fat diet. However, POMCCre/PPARγ-WT, but not POMCCre/PPARγ-P467L, mice increased body weight in response to rosiglitazone, a PPARγ agonist. These observations support the concept that alterations in PPARγ-driven mechanisms in POMC neurons can play a role in the regulation of metabolic homeostasis under certain dietary conditions.

Abstract 58: Angiotensin-(1-7) Mas Receptors In The Arcuate Nucleus Of The Hypothalamus Protect Against High Fat Diet-induced Insulin Resistance In Female Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Darren Mehay ◽  
Sarah Bingaman ◽  
Yuval Silberman ◽  
Amy Arnold
Keyword(s):  
Body Composition ◽  
Insulin Sensitivity ◽  
Energy Balance ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Metabolic Regulation ◽  
Arcuate Nucleus ◽  
Control Diet ◽  
High Fat ◽  
Metabolic Outcomes

Angiotensin (Ang)-(1-7) is a protective hormone of the renin-angiotensin system that improves insulin sensitivity, glucose tolerance, and energy balance in obese rodents. Our recent findings suggest that Ang-(1-7) activates mas receptors (MasR) in the arcuate nucleus of the hypothalamus (ARC), a brain region critical to control of energy balance and glucose homeostasis, to induce these positive metabolic effects. The distribution of MasR in the ARC and their role in metabolic regulation, however, is unknown. We hypothesized: (1) MasR are expressed in the ARC; and (2) deletion of ARC MasR leads to worsened metabolic outcomes following high fat diet (HFD). To test this, male and female C57Bl/6J mice were fed a 60% HFD or matched control diet ad libitum for 12 weeks. RNAscope in situ hybridization was performed on coronal ARC sections in rostral-middle-caudal regions to determine percentage of MasR positive neurons (n=5/group). In a second experiment, we assessed body composition and insulin and glucose tolerance in transgenic mice with deletion of MasR in ARC neurons (MasR-flox with AAV5-hsyn-GFP-Cre). RNAscope revealed a wide distribution on MasR-positive cells throughout the rostral to caudal extent of the ARC. The average percentage of MasR positive neurons was increased in females versus males, with HFD tending to increase MasR expression in both sexes (control diet male: 11±2; control diet female: 17±3; HFD male: 15±5; HFD female: 24±2; p sex : 0.030; p diet : 0.066; p int : 0.615; two-way ANOVA). Deletion of MasR in ARC neurons worsened insulin sensitivity in HFD but not control diet females (area under the curve for change in glucose from baseline: -1989±1359 HFD control virus vs. 2530±1762 HFD Cre virus; p=0.016), while fasting glucose, glucose tolerance, and body composition did not change. There was no effect of ARC MasR deletion on metabolic outcomes in control diet or HFD male mice. These findings suggest females have more MasR positive neurons in the ARC compared to males, which may be a sex-specific protective mechanism for glucose homeostasis. While further studies are needed to explore the role of ARC MasR in metabolic regulation, these findings support targeting Ang-(1-7) as an innovative strategy in obesity.

scholarly journals Tetrahydro iso-Alpha Acids from Hops Improve Glucose Homeostasis and Reduce Body Weight Gain and Metabolic Endotoxemia in High-Fat Diet-Fed Mice

PLoS ONE ◽  
2012 ◽  
Vol 7 (3) ◽  
pp. e33858 ◽  
Author(s):  
Amandine Everard ◽  
Lucie Geurts ◽  
Marie Van Roye ◽  
Nathalie M. Delzenne ◽  
Patrice D. Cani
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
High Fat ◽  
Reduce Body Weight ◽  
Metabolic Endotoxemia

scholarly journals Adult offspring of high-fat diet-fed dams can have normal glucose tolerance and body composition

2014 ◽  
Vol 5 (3) ◽  
pp. 229-239 ◽  
Author(s):  
K. M. Platt ◽  
R. J. Charnigo ◽  
K. J. Pearson
Keyword(s):  
Body Composition ◽  
Body Weight ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
High Fat Diet ◽  
High Fat ◽  
High Fat Diets ◽  
Normal Glucose ◽  
Fat Diets

Maternal high-fat diet consumption and obesity have been shown to program long-term obesity and lead to impaired glucose tolerance in offspring. Many rodent studies, however, use non-purified, cereal-based diets as the control for purified high-fat diets. In this study, primiparous ICR mice were fed purified control diet (10–11 kcal% from fat of lard or butter origin) and lard (45 or 60 kcal% fat) or butter (32 or 60 kcal% fat)-based high-fat diets for 4 weeks before mating, throughout pregnancy, and for 2 weeks of nursing. Before mating, female mice fed the 32 and 60% butter-based high-fat diets exhibited impaired glucose tolerance but those females fed the lard-based diets showed normal glucose disposal following a glucose challenge. High-fat diet consumption by female mice of all groups decreased lean to fat mass ratios during the 4th week of diet treatment compared with those mice consuming the 10–11% fat diets. All females were bred to male mice and pregnancy and offspring outcomes were monitored. The body weight of pups born to 45% lard-fed dams was significantly increased before weaning, but only female offspring born to 32% butter-fed dams exhibited long-term body weight increases. Offspring glucose tolerance and body composition were measured for at least 1 year. Minimal, if any, differences were observed in the offspring parameters. These results suggest that many variables should be considered when designing future high-fat diet feeding and maternal obesity studies in mice.

scholarly journals Obesity and Endocrine Dysfunction in Mice with Deletions of both Neuropeptide Y and Galanin

2004 ◽  
Vol 24 (7) ◽  
pp. 2978-2985 ◽  
Author(s):  
J. G. Hohmann ◽  
D. N. Teklemichael ◽  
D. Weinshenker ◽  
D. Wynick ◽  
D. K. Clifton ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Neuropeptide Y ◽  
High Fat Diet ◽  
Endocrine Dysfunction ◽  
Wild Type ◽  
High Fat ◽  
Metabolic Phenotypes ◽  
Obesity Phenotype ◽  
Compensatory Regulation

ABSTRACT Neuropeptide Y (NPY) and galanin have both been implicated in the regulation of body weight, yet mice bearing deletions of either of these molecules have unremarkable metabolic phenotypes. To investigate whether galanin and NPY might compensate for one another, we produced mutants lacking both neuropeptides (GAL−/−/NPY−/−). We found that male GAL−/−/NPY−/− mice ate significantly more and were much heavier (30%) than wild-type (WT) controls. GAL−/−/NPY−/− mice responded to a high-fat diet by gaining more weight than WT mice gain, and they were unable to regulate their weight normally after a change in diet. GAL−/−/NPY−/− mice had elevated levels of leptin, insulin, and glucose, and they lost more weight than WT mice during chronic leptin treatment. Galanin mRNA was increased in the hypothalamus of NPY−/− mice, providing evidence of compensatory regulation in single mutants. The disruption of energy balance observed in GAL−/−/NPY−/− double knockouts is not found in the phenotype of single knockouts of either molecule. The unexpected obesity phenotype may result from the dysregulation of the leptin and insulin systems that normally keep body weight within the homeostatic range.

Chronic benzylamine administration in the drinking water improves glucose tolerance, reduces body weight gain and circulating cholesterol in high-fat diet-fed mice

2010 ◽  
Vol 61 (4) ◽  
pp. 355-363 ◽  
Author(s):  
Zsuzsa Iffiú-Soltész ◽  
Estelle Wanecq ◽  
Almudena Lomba ◽  
Maria P. Portillo ◽  
Federica Pellati ◽  
...  
Keyword(s):  
Drinking Water ◽  
Body Weight ◽  
Weight Gain ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
High Fat

scholarly journals Hypothalamic Fkbp51 is induced by fasting, and elevated hypothalamic expression promotes obese phenotypes

2012 ◽  
Vol 302 (8) ◽  
pp. E987-E991 ◽  
Author(s):  
Linda Yang ◽  
Fumiko Isoda ◽  
Kelvin Yen ◽  
Steven P. Kleopoulos ◽  
William Janssen ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Glucose Tolerance ◽  
Negative Feedback ◽  
High Fat Diet ◽  
High Fat ◽  
Adeno Associated Virus ◽  
Fk506 Binding Protein ◽  
Hypothalamic Nuclei ◽  
Glucocorticoid Action

To discover hypothalamic genes that might play a role in regulating energy balance, we carried out a microarray screen for genes induced by a 48-h fast in male C57Bl/6J mouse hypothalamus. One such gene was Fkbp51 (FK506 binding protein 5; Locus NP_034350). The product of this gene is of interest because it blocks glucocorticoid action, suggesting that fasting-induced elevation of this gene in the hypothalamus may reduce glucocorticoid negative feedback, leading to elevated glucocorticoid levels, thus promoting obese phenotypes. Subsequent analysis demonstrated that a 48-h fast induces Fkbp51 in ventromedial, paraventricular, and arcuate hypothalamic nuclei of mice and rats. To assess if hypothalamic Fkbp51 promotes obesity, the gene was transferred to the hypothalamus via an adeno-associated virus vector. Within 2 wk following Fkbp51 overexpression, mice on a high-fat diet exhibited elevated body weight, without hyperphagia, relative to mice receiving the control mCherry vector. Body weight remained elevated for more than 8 wk and was associated with elevated corticosterone and impaired glucose tolerance. These studies suggest that elevated hypothalamic Fkbp51 promotes obese phenotypes.

scholarly journals Long-Term Supplementation With Fruits and Vegetables Curbs High-Fat Diet/Obesity-Induced Changes in Body Composition and Favorably Affects Blood T Cell Phenotype in Mice

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1126-1126
Author(s):  
Weimin Guo ◽  
Dayong Wu ◽  
Lijun Li ◽  
Edwin Ortega ◽  
Yankun Liu ◽  
...  
Keyword(s):  
Body Composition ◽  
Body Weight ◽  
Weight Gain ◽  
T Cell ◽  
Fat Mass ◽  
High Fat Diet ◽  
Cd4 Cells ◽  
High Fat ◽  
Cell Profile

Abstract Objectives Obesity is associated with impaired immune function. However, impact of obesity on blood T cell profile is not well studied. The objectives of this study were to investigate the effects of high fat diet (HFD)-induced obesity and long-term fruits and vegetable (FV) consumption on body composition and blood T cell profile. Methods This is partial report from an ongoing study. A total of 240 male C57BL/6J mice were randomly assigned to 4 groups: low fat control (LF-C) or high-fat control (HF-C) diet alone, or together with 15% of a unique mixture of FV (w/w, equivalent to 7–9 servings F&V/d for human) (LF-FV or HF-FV). The feeding will continue until 50% mortality is reached in one group. Body weight, body composition (using MRI), and blood T cell profile (using FACS) are monitored longitudinally at different time points. The results reported here are those assessed when mice were 7 months old. Results After 7 months of feeding, mice fed HF-C gained more weight compared to those fed LF-C. Mice fed HF-FV or LF-FV diets had significantly reduced weight gain and fat mass, and higher muscle mass compared to those fed HF-C or LF-C diet, respectively. Mice fed HF-C also had significantly lower percentage of blood CD3+, CD4+, and CD8 + T cells compared with the LF-C. FV supplementation prevented HFD-induced decrease in percentage of CD3+ and CD4+ cells. Furthermore, both % CD3+ and CD4+ cells were negatively correlated with body weight (P < 0.001) or percentage of fat mass (P < 0.001), and positively associated with percentage of lean mass (P < 0.001). Conclusions Our results suggest that consuming large amounts of a unique mixture of F&V curbs HFD-induced body weight gain, reduces fat mass, and favorably affects blood T cell population. Ongoing studies will assess these analytes when mice are 16 months old, and again when one group reaches 50% mortality, and determine their correlations with functional measures of T cell response, host resistance to infection, health span, and mortality. Funding Sources This study was supported by the U.S. Department of Agriculture – Agricultural Research Service (ARS), under Agreement No. 58–1950-4–004.

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