scholarly journals Ostα−/−mice exhibit altered expression of intestinal lipid absorption genes, resistance to age-related weight gain, and modestly improved insulin sensitivity

2014 ◽  
Vol 306 (5) ◽  
pp. G425-G438 ◽  
Author(s):  
Sadie G. Wheeler ◽  
Christine L. Hammond ◽  
François R. Jornayvaz ◽  
Varman T. Samuel ◽  
Gerald I. Shulman ◽  
...  
Keyword(s):  
Weight Gain ◽  
Insulin Sensitivity ◽  
Bile Acids ◽  
Lipid Absorption ◽  
Acute Administration ◽  
Wild Type ◽  
Altered Expression ◽  
Male And Female ◽  
Fat Accumulation ◽  
Age Related

The organic solute transporter OSTα-OSTβ is a key transporter for the efflux of bile acids across the basolateral membrane of ileocytes and the subsequent return of bile acids to the liver. Ostα−/−mice exhibit reduced bile acid pools and impaired lipid absorption. In this study, wild-type and Ostα−/−mice were characterized at 5 and 12 mo of age. Ostα−/−mice were resistant to age-related weight gain, body fat accumulation, and liver and muscle lipid accumulation, and male Ostα−/−mice lived slightly longer than wild-type mice. Caloric intake and activity levels were similar for Ostα−/−and wild-type male mice. Fecal lipid excretion was increased in Ostα−/−mice, indicating that a defect in lipid absorption contributes to decreased fat accumulation. Analysis of genes involved in intestinal lipid absorption revealed changes consistent with decreased dietary lipid absorption in Ostα−/−animals. Hepatic expression of cholesterol synthetic genes was upregulated in Ostα−/−mice, showing that increased cholesterol synthesis partially compensated for reduced dietary cholesterol absorption. Glucose tolerance was improved in male Ostα−/−mice, and insulin sensitivity was improved in male and female Ostα−/−mice. Akt phosphorylation was measured in liver and muscle tissue from mice after acute administration of insulin. Insulin responses were significantly larger in male and female Ostα−/−than wild-type mice. These findings indicate that loss of OSTα-OSTβ protects against age-related weight gain and insulin resistance.

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 NPY Deficiency Prevents Postmenopausal Adiposity by Augmenting Estradiol-Mediated Browning

2018 ◽  
Vol 75 (6) ◽  
pp. 1042-1049
Author(s):  
Seongjoon Park ◽  
Erkhembayar Nayantai ◽  
Toshimitsu Komatsu ◽  
Hiroko Hayashi ◽  
Ryoichi Mori ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Fat Metabolism ◽  
Male Mice ◽  
Wild Type ◽  
Male And Female ◽  
Female Mice ◽  
Age Related ◽  
Promising Target ◽  
Intracellular Mechanism

Abstract The orexigenic hormone neuropeptide Y (NPY) plays a pivotal role in the peripheral regulation of fat metabolism. However, the mechanisms underlying the effects of sex on NPY function have not been extensively analyzed. In this study, we examined the effects of NPY deficiency on fat metabolism in male and female mice. Body weight was slightly decreased, whereas white adipose tissue (WAT) mass was significantly decreased as the thermogenic program was upregulated in NPY-/- female mice compared with that in wild-type mice; these factors were not altered in response to NPY deficiency in male mice. Moreover, lack of NPY resulted in an increase in luteinizing hormone (LH) expression in the pituitary gland, with concomitant activation of the estradiol-mediated thermogenic program in inguinal WAT, and alleviated age-related modification of adiposity in female mice. Taken together, these data revealed a novel intracellular mechanism of NPY in the regulation of fat metabolism and highlighted the sexual dimorphism of NPY as a promising target for drug development to reduce postmenopausal adiposity.

Intestinal scavenger receptor class B type I as a novel regulator of chylomicron production in healthy and diet-induced obese states

2015 ◽  
Vol 309 (5) ◽  
pp. G350-G359 ◽  
Author(s):  
Marsel Lino ◽  
Sarah Farr ◽  
Chris Baker ◽  
Mark Fuller ◽  
Bernardo Trigatti ◽  
...  
Keyword(s):  
Weight Gain ◽  
Scavenger Receptor ◽  
Lipid Absorption ◽  
Type I ◽  
Wild Type ◽  
High Fat ◽  
Diabetic Dyslipidemia ◽  
Scavenger Receptor Class ◽  
Class B ◽  
Postprandial Hypertriglyceridemia

The small intestine contributes to diabetic dyslipidemia through the overproduction of apolipoprotein B48 (apoB48)-containing chylomicron particles. An important regulator of chylomicron generation is dietary lipid absorption, underlining the potential involvement of intestinal lipid transporters for developing dyslipidemia. Intestinal expression of scavenger receptor class B type I (SR-BI) has been found to be upregulated in animal models of insulin resistance. Here we characterized the potential importance of SR-BI in contributing to chylomicron production and postprandial hypertriglyceridemia in vivo. Postprandial triglyceride (TG)-rich lipoprotein (TRL) production was characterized in hamsters treated with the SR-BI inhibitor to block lipid transport-1 (BLT-1) under healthy conditions or conditions of diet-induced obesity and dyslipidemia. BLT-1 (1 mg/kg) or vehicle was administered acutely in chow-fed hamsters or gavaged twice daily over 10 days during high-fructose, high-fat, high-cholesterol (FFC) feeding. Effects of acute SR-BI inhibition by BLT-1 were confirmed in healthy fat-loaded rats. Finally, plasma lipid levels were compared between SR-BI−/− mice and their wild-type counterparts fed either chow or a 12-wk high-fat diet. Acute BLT-1 treatment reduced postprandial plasma and TRL TG levels in healthy hamsters and rats. Chronic BLT-1 treatment of FFC-fed hamsters blunted diet-induced weight gain and fasting hypertriglyceridemia, and lowered postprandial TRL-TG, -cholesterol, and -apoB48 levels. Finally, SR-BI−/− mice displayed lower plasma and TRL TG levels relative to wild type, and diet-induced weight gain and postprandial hypertriglyceridemia were hindered in SR-BI−/− mice. We conclude that intestinal SR-BI is a critical regulator of postprandial lipoprotein production, emphasizing its potential as a target for preventing diabetic dyslipidemia.

scholarly journals Knockdown of angiopoietin-like 2 mimics the benefits of intermittent fasting on insulin responsiveness and weight loss

2017 ◽  
Vol 243 (1) ◽  
pp. 45-49 ◽  
Author(s):  
Cécile Martel ◽  
Anthony Pinçon ◽  
Alexandre Maxime Bélanger ◽  
Xiaoyan Luo ◽  
Marc-Antoine Gillis ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Energy Intake ◽  
Intermittent Fasting ◽  
Wild Type ◽  
Beneficial Effects ◽  
Obesity And Diabetes ◽  
Ad Libitum ◽  
Insulin Responsiveness

Angiopoietin-like 2 (ANGPTL2) is an inflammatory adipokine linking obesity to insulin resistance. Intermittent fasting, on the other hand, is a lifestyle intervention able to prevent obesity and diabetes but difficult to implement and maintain. Our objectives were to characterize a link between ANGPTL2 and intermittent fasting and to investigate whether the knockdown of ANGPTL2 reproduces the benefits of intermittent fasting on weight gain and insulin responsiveness in knockdown and wild-type littermates mice. Intermittent fasting, access to food ad libitum once every other day, was initiated at the age of three months and maintained for four months. Intermittent fasting decreased by 63% (p < 0.05) gene expression of angptl2 in adipose tissue of wild-type mice. As expected, intermittent fasting improved insulin sensitivity (p < 0.05) and limited weight gain (p < 0.05) in wild-type mice. Knockdown mice fed ad libitum, however, were comparable to wild-type mice following the intermittent fasting regimen: insulin sensitivity and weight gain were identical, while intermittent fasting had no additional impact on these parameters in knockdown mice. Energy intake was similar between both wild-type fed intermittent fasting and ANGPTL2 knockdown mice fed ad libitum, suggesting that intermittent fasting and knockdown of ANGPTL2 equally lower feeding efficiency. These results suggest that the reduction of ANGPTL2 could be a useful and promising strategy to prevent obesity and insulin resistance, although further investigation of the mechanisms linking ANGPTL2 and intermittent fasting is warranted. Impact statement Intermittent fasting is an efficient diet pattern to prevent weight gain and improve insulin sensitivity. It is, however, a difficult regimen to follow and compliance is expected to be very low. In this work, we demonstrate that knockdown of ANGPTL2 in mice fed ad libitum mimics the beneficial effects of intermittent fasting on weight gain and insulin sensitivity in wild-type mice. ANGPTL2 is a cytokine positively associated with fat mass in humans, which inactivation in mice improves resistance to a high-fat metabolic challenge. This study provides a novel pathway by which IF acts to limit obesity despite equivalent energy intake. The development of a pharmacological ANGPTL2 antagonist could provide an efficient tool to reduce the burden of obesity.

Disruption of the murine intestinal alkaline phosphatase gene Akp3 impairs lipid transcytosis and induces visceral fat accumulation and hepatic steatosis

2007 ◽  
Vol 292 (5) ◽  
pp. G1439-G1449 ◽  
Author(s):  
Takanari Nakano ◽  
Ikuo Inoue ◽  
Iwao Koyama ◽  
Kenta Kanazawa ◽  
Koh-ichi Nakamura ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Body Weight ◽  
Weight Gain ◽  
Visceral Fat ◽  
Corn Oil ◽  
Body Weight Gain ◽  
Lipid Absorption ◽  
Wild Type ◽  
Intestinal Alkaline Phosphatase ◽  
Visceral Fat Accumulation

Intestinal alkaline phosphatase (IAP) is involved in the process of fat absorption, a conclusion confirmed by an altered lipid transport and a faster body weight gain from 10 to 30 wk in both male and female mice with a homozygous null mutation of the IAP coding gene ( Akp3−/− mice). This study was aimed to delineate morphologically and quantitatively the accelerated lipid absorption in male Akp3−/− mice. Feeding a corn oil bolus produced an earlier peak of triacylglycerol in serum (2 vs. 4 h for Akp3−/− and wild-type mice, respectively) and an approximately twofold increase in serum triacylglycerol concentration in Akp3−/− mice injected with a lipolysis inhibitor, Triton WR-1339. A corn oil load induced the threefold enlargement of the Golgi vacuoles in male wild-type mice but not in Akp3−/− mice, indicating that absorbed lipids rarely reached the Golgi complex and that the transcytosis of lipid droplets does not follow the normal pathway in male Akp3−/− mice. Force feeding an exaggerated fat intake by a 30% fat chow for 10 wk induced obesity in both male Akp3−/− and wild-type mice, and therefore no phenotypic difference was observed between the two. On the other hand, the forced high-fat chow induced an 18% greater body weight gain, hepatic steatosis, and visceral fat accumulation in female Akp3−/− mice but not in female wild-type controls. These results provide further evidence that IAP is involved in the regulation of the lipid absorption process and that its absence leads to progressive metabolic abnormalities in certain fat-forced conditions.

scholarly journals Chromogranin A plays a crucial role in the age-related development of insulin resistance and hypertension

2021 ◽  
Author(s):  
Matthew A Liu ◽  
Suborno Jati ◽  
Kechun Tang ◽  
Geert van den Bogaart ◽  
Gourisankar Ghosh ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Chromogranin A ◽  
Mitochondrial Fission ◽  
Tnf Alpha ◽  
Wild Type ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Age Related ◽  
Related Development

Aging is associated with the development of metabolic disorders, including insulin resistance and hypertension. Young mice that are negative for the neuroendocrine prohormone Chromogranin A (CgA knockout, CgA-KO) display two opposite aging phenotypes: hypertension but heightened insulin sensitivity. We determined these phenotypes in aging CgA mice. In comparison, aging wild-type (WT) mice gradually lost glucose tolerance and insulin sensitivity. Moreover, while aging WT mice had increased inflammation with higher plasma TNF-alpha;, IFN-gamma; and CCL2 and increased mitochondrial fission, these phenotypes were the opposite in aging CgA-KO mice. CgA-KO mice also showed increased expression of mitochondrial and nuclear-encoded complex I genes, implying that they were healthier than WT mice. Most intriguingly, the hypertension in CgA-KO mice was spontaneously reversed with aging. Supplementation of CgA-KO mice with pancreastatin, a hyperglycemic peptide produced from CgA by proteolysis, increased both blood glucose levels and blood pressure, implicating hyperglycemia, and hypertension. We conclude that age-related insulin resistance and hypertension are caused by CgA.

scholarly journals Absence of GIP secretion alleviates age-related obesity and insulin resistance

2020 ◽  
Vol 245 (1) ◽  
pp. 13-20 ◽  
Author(s):  
Yoshinori Kanemaru ◽  
Norio Harada ◽  
Satoko Shimazu-Kuwahara ◽  
Shunsuke Yamane ◽  
Eri Ikeguchi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Fat Mass ◽  
Body Weight Gain ◽  
Tolerance Test ◽  
Mrna Levels ◽  
Feeding Condition ◽  
Age Related

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin secreted from enteroendocine K cells after nutrient ingestion. Fat strongly induces GIP secretion, and GIP hypersecretion is involved in high-fat diet-induced obesity and insulin resistance. Aging also induces GIP hypersecretion, but its effect on body weight gain and insulin sensitivity remains unclear. In the present study, we investigated the effect of GIP on age-related body weight gain and insulin resistance using GIP-knockout homozygous (GIP−/−) and heterozygous (GIP+/−) mice, which have entirely absent and 50% reduced GIP secretion compared to wild-type (WT) mice, respectively. Under 12% fat-containing normal diet feeding condition, body weight was significantly lower in GIP−/− mice compared to that in WT and GIP+/− mice from 38 weeks of age, while there was no significant difference between WT and GIP+/− mice. Visceral and s.c. fat mass were also significantly lower in GIP−/− mice compared to those in WT and GIP+/− mice. During oral glucose tolerance test, blood glucose levels did not differ among the three groups. Insulin levels were significantly lower in GIP−/− mice than those in WT and GIP+/− mice. During insulin tolerance test, GIP−/− mice showed higher insulin sensitivity than that of WT and GIP+/− mice. Adiponectin mRNA levels were increased and leptin mRNA levels tended to be decreased in adipose tissue of GIP−/− mice. These results demonstrate that GIP is involved in age-related obesity and insulin resistance and that inhibition of GIP secretion alleviates age-related fat mass gain and insulin resistance under carbohydrate-based diet feeding condition.

Longitudinal study of urinary excretion of phosphate, calcium, and uric acid in mutant NHERF-1 null mice

2006 ◽  
Vol 290 (4) ◽  
pp. F838-F843 ◽  
Author(s):  
Edward J. Weinman ◽  
Viresh Mohanlal ◽  
Nicholas Stoycheff ◽  
Fengying Wang ◽  
Deborah Steplock ◽  
...  
Keyword(s):  
Uric Acid ◽  
Urinary Excretion ◽  
Proximal Tubule ◽  
Young Male ◽  
Wild Type ◽  
Protein Targets ◽  
Male And Female ◽  
Age Related ◽  
Time Period ◽  
Apical Membranes

NHERF-1 binds numerous renal protein targets, including the proximal tubule transporters Na+/H+ exchanger 3 (NHE3) and Na+-phosphate cotransporter 2a (Npt2a). Young NHERF-1−/− male mice display defective targeting of Npt2a to apical membranes in the renal proximal tubule and manifest hypophosphatemia and increased urinary excretion of phosphate. The present studies describe the changes in the urinary excretion of phosphate, calcium, uric acid, and sodium in male and female wild-type and NHERF-1 null mice over a time period from 12 to 54 wk of age. Young male and female NHERF-1−/− mice demonstrated increased urinary excretion of phosphate and urine phosphate/creatinine ratios. There was an age-related decline in the phosphate/creatinine ratio in mutant mice such that there were no differences between wild-type and NHERF-1−/− by 24 to 30 wk of age despite the continued presence of hypophosphatemia. Male and female NHERF-1 null mice also demonstrate increased urine calcium/creatinine and uric acid/creatinine ratios compared with wild-type controls. These studies indicate defects in the renal tubule transport of phosphate, calcium, and uric acid in NHERF-1−/− male and female mice that could account for the increased deposition of calcium in the papilla of null mice.

Sign in / Sign up

Export Citation Format

Share Document