Transgenic Rescue of Adipocyte Glucose-dependent Insulinotropic Polypeptide Receptor Expression Restores High Fat Diet-induced Body Weight Gain

Ugleholdt, Randi; Pedersen, Jens; Bassi, Maria Rosaria; Füchtbauer, Ernst‐Martin; Jørgensen, Signe Marie; Kissow, Hannelouise; Nytofte, Nikolaj; Poulsen, Steen Seier; Seino, Yutaka; Thams, Peter; Holst, Peter Johannes; Holst, Jens J.

doi:10.1074/jbc.m111.311779

Cited by 41 publications

(35 citation statements)

References 65 publications

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“…Moreover, the fatty acid synthesis-related genes SREBP-1 and FAS were downregulated in the liver. GIPR expression was also shown to be absent in the liver (40,41,45). Even though the expression of both the SREBP-1c and FAS genes was previously reported to be directly regulated by insulin (28), a decrease in the expression of these genes due to the ingestion of TASP may also be insulin-independent because nonfasting blood insulin levels were not altered by the ingestion of TASP.…”

Section: Discussionmentioning

confidence: 86%

Triterpene alcohols and sterols from rice bran lower postprandial glucose-dependent insulinotropic polypeptide release and prevent diet-induced obesity in mice

Fukuoka

Okahara

Hashizume

et al. 2014

Journal of Applied Physiology

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Obesity is now a worldwide health problem. Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone that is secreted following the ingestion of food and modulates energy metabolism. Previous studies reported that lowering diet-induced GIP secretion improved energy homeostasis in animals and humans, and attenuated diet-induced obesity in mice. Therefore, food-derived GIP regulators may be used in the development of foods that prevent obesity. Rice bran oil and its components are known to have beneficial effects on health. Therefore, the aim of the present study was to clarify the effects of the oil-soluble components of rice bran on postprandial GIP secretion and obesity in mice. Triterpene alcohols [cycloartenol (CA) and 24-methylene cycloartanol (24Me)], β-sitosterol, and campesterol decreased the diet-induced secretion of GIP in C57BL/6J mice. Mice fed a high-fat diet supplemented with a triterpene alcohol and sterol preparation (TASP) from rice bran for 23 wk gained less weight than control mice. Indirect calorimetry revealed that fat utilization was higher in TASP-fed mice than in control mice. Fatty acid oxidation-related gene expression in the muscles of mice fed a TASP-supplemented diet was enhanced, whereas fatty acid synthesis-related gene expression in the liver was suppressed. The treatment of HepG2 cells with CA and 24Me decreased the gene expression of sterol regulatory element-binding protein (SREBP)-1c. In conclusion, we clarified for the first time that triterpene alcohols and sterols from rice bran prevented diet-induced obesity by increasing fatty acid oxidation in muscles and decreasing fatty acid synthesis in the liver through GIP-dependent and GIP-independent mechanisms.

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Section: Discussionmentioning

confidence: 86%

Triterpene alcohols and sterols from rice bran lower postprandial glucose-dependent insulinotropic polypeptide release and prevent diet-induced obesity in mice

Fukuoka

Okahara

Hashizume

et al. 2014

Journal of Applied Physiology

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“…44 Our data could therefore suggest that elevated postprandial GIP levels may drive a postprandial hyperglucagonemic response in patients treated with antipsychotics. Interestingly, GIP also has adipogenic properties, 45 and positive correlations between postprandial GIP levels in plasma and BMI have been reported in patients with type 2 diabetes. 46 Thus, it may be speculated that elevated GIP levels may contribute to antipsychotic-induced weight gain.…”

Section: Discussionmentioning

confidence: 99%

Glucometabolic Hormones and Cardiovascular Risk Markers in Antipsychotic-Treated Patients

Ebdrup¹,

Knop²,

Madsen³

et al. 2014

J. Clin. Psychiatry

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Objective: Treatment with antipsychotic drugs is widely associated with metabolic side effects such as weight gain and disturbed glucose metabolism, but the pathophysiologic mechanisms are unclear.Method: Fifty nondiabetic (fasting plasma glucose ≤ 7.0 mmol/L), antipsychotic-treated male patients (ICD-10 diagnosis code F20, F21, F22, F25, F28, or F60; mean ± SD age = 33.0 ± 6.7 years; body mass index [BMI; kg/ m 2 ] = 26.0 ± 4.7; waist circumference = 95.9 ± 13.3 cm; glycated hemoglobin A 1c [HbA 1c ] = 5.7% ± 0.3%) and 93 age-and waist circumference-matched healthy male controls (age = 33 ± 7.3 years; BMI = 26.1 ± 3.9; waist circumference = 94.6 ± 11.9 cm; HbA 1c = 5.7% ± 0.3%) participated in this cross-sectional study. Blood was sampled in the fasting state and 90 minutes after ingestion of a standardized liquid meal (2,268 kJ). The primary outcomes were glucometabolic hormones and cardiovascular risk markers. Data were collected between March 2008 and February 2010.Results: Compared to healthy controls, patients were characterized by elevated fasting levels of proinsulin, C-peptide, and glucose-dependent insulinotropic polypeptide (GIP) (P < .05) and higher postprandial levels of insulin, proinsulin, C-peptide, and GIP (P ≤ .02). Also, patients exhibited elevated plasma levels of C-reactive protein and signs of dyslipidemia. Fasting plasma levels of insulin, glucagon, glucagon-like peptide-1 (GLP-1), ghrelin, leptin, adiponectin, tumor necrosis factor-α, plasminogen activator inhibitor-1, and interleukin-6 and postprandial levels of glucagon, GLP-1, ghrelin, leptin, and adiponectin did not differ between groups. Conclusions:Presenting with an insulin resistant-like pattern, including beta cell hypersecretion and elevated GIP levels, nondiabetic antipsychotic-treated patients display emerging signs of dysmetabolism and a compromised cardiovascular risk profile. The appetite-regulating hormones GLP-1 and ghrelin appear not to be influenced by antipsychotic treatment. Our findings provide new clinical insight into the pathophysiology associated with metabolic side effects of antipsychotic treatment and put emphasis on the importance of implementing metabolic screening into psychiatric practice.Trial Registration: ClinicalTrials.gov identifier NCT00627757 Clin Psychiatry 2014;75(9):e899-e905 J

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“…The above interpretations were generated by dividing the weight gain when fed the high-fat diet by the weight gain when fed the control diet ( fig. 10 i) [123] . However, this approach generates an anomalous result, because the response to the high-fat diet in this case is greatest in the aP2-/-mice, which should have no active GIPR of either human or mouse origin and hence should not differ from the wild-type KO animals.…”

Section: Sh2b1mentioning

confidence: 99%

“…culture is enhanced when insulin is present [43] , indicating both actions may play a role. To address this issue in vivo , mice were generated that had targeted tissue-specific expression of human GIPR in only the adipocytes (aP2+/-) or in only the β cells (RIP+/-) [123] . By crossing these mice with GIPR KO mice, they generated mice that expressed human GIPR in adipocytes or β cells only.…”

Section: Sh2b1mentioning

confidence: 99%

“…This suggests that both direct and indirect modes of action for GIPR on fat storage play an important role. Ugleholdt et al [123] additionally suggested that the differences in weight gain on a high-fat diet were due to differences in lean rather than fat tissue (see original paper fig. 3), although this again relies on dividing the changes under high-fat feeding by those observed under the control diet, which produces similar anomalous high responses in the aP2-/-group.…”

Section: Sh2b1mentioning

confidence: 99%

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Functional Analysis of Seven Genes Linked to Body Mass Index and Adiposity by Genome-Wide Association Studies: A Review

Speakman

2013

Hum Hered

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Genome-wide association studies (GWAS) have identified a total of about 40 single nucleotide polymorphisms (SNPs) that show significant linkage to body mass index, a widely utilised surrogate measure of adiposity. However, only 8 of these associations have been confirmed by follow-up GWAS using more sophisticated measures of adiposity (computed tomography). Among these 8, there is a SNP close to the gene FTO which has been the subject of considerable work to diagnose its function. The remaining 7 SNPs are adjacent to, or within, the genes NEGR1, TMEM18, ETV5, FLJ35779, LINGO2, SH2B1 and GIPR, most of which are less well studied than FTO, particularly in the context of obesity. This article reviews the available data on the functions of these genes, including information gleaned from studies in humans and animal models. At present, we have virtually no information on the putative mechanism associating the genes FLJ35779 and LINGO2 to obesity. All of these genes are expressed in the brain, and for 2 of them (SH2B1 and GIPR), a direct link to the appetite regulation system is known. SH2B1 is an enhancer of intracellular signalling in the JAK-STAT pathway, and GIPR is the receptor for an appetite-linked hormone (GIP) produced by the alimentary tract. NEGR1, ETV5 and SH2B1 all have suggested roles in neurite outgrowth, and hence SNPs adjacent to these genes may affect development of the energy balance circuitry. Although the genes have central patterns of gene expression, implying a central neuronal connection to energy balance, for at least 4 of them (NEGR1, TMEM18, SH2B1 and GIPR), there are also significant peripheral functions related to adipose tissue biology. These functions may contribute to their effects on the obese phenotype.

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Transgenic Rescue of Adipocyte Glucose-dependent Insulinotropic Polypeptide Receptor Expression Restores High Fat Diet-induced Body Weight Gain

Cited by 41 publications

References 65 publications

Triterpene alcohols and sterols from rice bran lower postprandial glucose-dependent insulinotropic polypeptide release and prevent diet-induced obesity in mice

Triterpene alcohols and sterols from rice bran lower postprandial glucose-dependent insulinotropic polypeptide release and prevent diet-induced obesity in mice

Glucometabolic Hormones and Cardiovascular Risk Markers in Antipsychotic-Treated Patients

Functional Analysis of Seven Genes Linked to Body Mass Index and Adiposity by Genome-Wide Association Studies: A Review

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