1814-P: JAZF1 Knockout Mice Are Protected against Diet-Induced Metabolic Syndrome

Intake of sugars, especially the fructose component, is strongly associated with the development of obesity and metabolic syndrome, but the relative role of taste versus metabolism in driving preference, intake, and metabolic outcome is not fully understood. We aimed to evaluate the preference for sweet substances and the tendency to develop metabolic syndrome in response to these sugars in mice lacking functional taste signaling [P2X2 (P2X purinoreceptor 2)/P2X3 (P2X purinoreceptor 3) double knockout mice (DKO)] and mice unable to metabolize fructose (fructokinase knockout mice). Of interest, our data indicate that despite their inability to taste sweetness, P2X2/3 DKO mice still prefer caloric sugars (including fructose and glucose) to water in long-term testing, although with diminished preference compared with control mice. Despite reduced intake of caloric sugars by P2X2/3 DKO animals, the DKO mice still show increased levels of the sugar-dependent hormone FGF21 (fibroblast growth factor 21) in plasma and liver. Despite lower sugar intake, taste-blind mice develop severe features of metabolic syndrome due to reduced sensitivity to leptin, reduced ability to mobilize and oxidize fats, and increased hepatic de novo lipogenesis. In contrast to P2X2/3 DKO and wild-type mice, fructokinase knockout mice, which cannot metabolize fructose and are protected against fructose-induced metabolic syndrome, demonstrate reduced preference and intake for all fructose-containing sugars tested but not for glucose or artificial sweeteners. Based on these observations, we conclude that sugar can induce metabolic syndrome in mice independently of its sweet properties. Furthermore, our data demonstrate that the metabolism of fructose is necessary for sugar to drive intake and preference in mice.

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Hexose-6-phosphate dehydrogenase: linking endocrinology and metabolism in the endoplasmic reticulum

Journal of Molecular Endocrinology ◽

10.1677/jme-08-0156 ◽

2008 ◽

Vol 42 (4) ◽

pp. 283-289 ◽

Cited By ~ 29

Author(s):

Gábor Bánhegyi ◽

Miklós Csala ◽

Angelo Benedetti

Keyword(s):

Metabolic Syndrome ◽

Endoplasmic Reticulum ◽

Knockout Mice ◽

Metabolic Regulation ◽

Nutrient Sensing ◽

Intermediary Metabolism ◽

Recent Developments

Hexose-6-phosphate dehydrogenase (H6PD) got into the focus of interest due to its role in the prereceptorial activation of glucocorticoids, which has been implicated in the pathomechanism of metabolic syndrome. Genetic observations, results gained in H6PD knockout mice, and studies on differentiating adipocytes demonstrated the importance of the enzyme in metabolic regulation. A nutrient-sensing function can be postulated for the enzyme, which links metabolism to endocrinology in the endoplasmic reticulum. This review provides an overview of the recent developments concerning the enzyme and its impact on various branches of the intermediary metabolism, which make it an important subject for the research on obesity, diabetes, and metabolic syndrome.

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Improvement of metabolic syndrome by irbesartan via the PPARγ/HGF pathway in apolipoprotein E knockout mice

Biomedical Reports ◽

10.3892/br.2012.28 ◽

2012 ◽

Vol 1 (1) ◽

pp. 65-70 ◽

Cited By ~ 6

Author(s):

AMARNATH CHATTERJEE ◽

HIROSHI KUSUNOKI ◽

YOSHIAKI TANIYAMA ◽

HIROMI RAKUGI ◽

RYUICHI MORISHITA

Keyword(s):

Metabolic Syndrome ◽

Apolipoprotein E ◽

Knockout Mice ◽

Apolipoprotein E Knockout Mice

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Male 11β-HSD1 Knockout Mice Fed Trans-Fats and Fructose Are Not Protected From Metabolic Syndrome or Nonalcoholic Fatty Liver Disease

Endocrinology ◽

10.1210/en.2016-1357 ◽

2016 ◽

Vol 157 (9) ◽

pp. 3493-3504 ◽

Cited By ~ 9

Author(s):

Dean P. Larner ◽

Stuart A. Morgan ◽

Laura L. Gathercole ◽

Craig L. Doig ◽

Phil Guest ◽

...

Keyword(s):

Metabolic Syndrome ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Knockout Mice ◽

Fatty Liver Disease ◽

Trans Fats ◽

Nonalcoholic Fatty Liver

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Apo A1 Mimetic Rescues the Diabetic Phenotype of HO-2 Knockout Mice via an Increase in HO-1 Adiponectin and LKBI Signaling Pathway

International Journal of Hypertension ◽

10.1155/2012/628147 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 12

Author(s):

Jian Cao ◽

Nitin Puri ◽

Komal Sodhi ◽

Lars Bellner ◽

Nader G. Abraham ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Blood Pressure ◽

Metabolic Syndrome ◽

Knockout Mice ◽

Elevated Blood ◽

Adipose Tissue Dysfunction ◽

Mimetic Peptides ◽

Metabolic Imbalance ◽

Expression And Activity

Insulin resistance, with adipose tissue dysfunction, is one of the hallmarks of metabolic syndrome. We have reported a metabolic syndrome-like phenotype in heme oxygenase (HO)-2 knockout mice, which presented with concurrent HO-1 deficiency and were amenable to rescue by an EET analog. Apo A-I mimetic peptides, such as L-4F, have been shown to induce HO-1 expression and decrease oxidative stress and adiposity. In this study we aimed to characterize alleviatory effects of HO-1 induction (if any) on metabolic imbalance observed in HO-2 KO mice. In this regard, HO-2(−/−)mice were injected with 2 mg/kg/day L-4F, or vehicle, i.p., for 6 weeks. As before, compared to WT animals, the HO-2 null mice were obese, displayed insulin resistance, and had elevated blood pressure. These changes were accompanied by enhanced tissue (hepatic) oxidative stress along with attenuation of HO-1 expression and activity and reduced adiponectin, pAMPK, and LKB1 expression. Treatment with L-4F restored HO-1 expression and activity and increased adiponectin, LKB1, and pAMPK in the HO-2(−/−)mice. These alterations resulted in a decrease in blood pressure, insulin resistance, blood glucose, and adiposity. Taken together, our results show that a deficient HO-1 response, in a state with reduced HO-2 basal levels, is accompanied by disruption of metabolic homeostasis which is successfully restored by an HO-1 inducer.

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