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      Dietary fat and gut microbiota interactions determine diet-induced obesity in mice

      research-article
      1 , 2 , 8 , 1 , 2 , 1 , 2 , 3 , 1 , 4 , 1 , 5 , 1 , 6 , 6 , 4 , 1 , 3 , 7 , 1 , 5 , 1 , 1 , 2 ,
      Molecular Metabolism
      Elsevier
      Germfree, Energy balance, Diet-induced obesity resistance, High-fat diet, Abcg5, ATP-binding cassette sub-family G member 5, Abcg8, ATP-binding cassette sub-family G member 8, Actb, beta actin, Akr1d1, aldo-keto-reductase family member 1, ANOVA, analysis of variance, BMR, basal metabolic rate, CD, control diet, CA, cholic acid, CDCA, chenodeoxycholic acid, CIDEA, cell death inducing DFFA-like effector, COX4, cytochrome c oxidase subunit 4, Cyp7a1, cholesterol 7 alpha-hydroxylase, Cyp27a1, cholesterol 27 alpha-hydroxylase, DCA, deoxycholic acid, Dhcr7, 7-dehydrocholesterol reductase, DIO, diet-induced obesity, DEE, daily energy expenditure, Eef2, eukaryotic elongation factor 2, FT-ICR-MS, Fourier transform-Ion Cyclotron Resonance-Mass Spectrometry, FT-IR, Fourier transform-infrared spectroscopy, GF, germfree, GUSB, beta-glucuronidase, HDCA, hyodeoxycholic acid, Hmgcr, 3-hydroxy-3-methylglutaryl Coenzyme A reductase, Hmgcs, 3-hydroxy-3-methylglutaryl Coenzyme A synthase 1, HP, heat production, Hprt1, hypoxanthine guanine phosphoribosyl transferase, Hsd11b1, hydroxysteroid (11-β) dehydrogenase 1, Hsp90, heat shock protein 90, Ldlr, low density lipoprotein receptor, LHFD, high-fat diet based on lard, MCA, muricholic acid, Nr1h2, nuclear receptor subfamily 1, group H, member 2 (liver X receptor β), Nr1h3, nuclear receptor subfamily 1, group H, member 3 (liver X receptor α), Nr1h4, nuclear receptor subfamily 1, group H, member 4 (farnesoid X receptor α), PHFD, high-fat diet based on palm oil, PRDM16, PR domain containing 16, qPCR, quantitative real-time polymerase chain reaction, SPF, specific pathogen free, Srebf1, sterol regulatory element binding transcription factor 1, TCA, taurocholic acid, Tf2b, transcription factor II B, TMCA, Tauromuricholic acid, UCP1, uncoupling protein 1, UDCA, ursodeoxycholic acid, UPLC-TOF-MS, ultraperformance liquid chromatography-time of flight-mass spectrometry

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          Abstract

          Objective

          Gut microbiota may promote positive energy balance; however, germfree mice can be either resistant or susceptible to diet-induced obesity (DIO) depending on the type of dietary intervention. We here sought to identify the dietary constituents that determine the susceptibility to body fat accretion in germfree (GF) mice.

          Methods

          GF and specific pathogen free (SPF) male C57BL/6N mice were fed high-fat diets either based on lard or palm oil for 4 wks. Mice were metabolically characterized at the end of the feeding trial. FT-ICR-MS and UPLC-TOF-MS were used for cecal as well as hepatic metabolite profiling and cecal bile acids quantification, respectively. Hepatic gene expression was examined by qRT-PCR and cecal gut microbiota of SPF mice was analyzed by high-throughput 16S rRNA gene sequencing.

          Results

          GF mice, but not SPF mice, were completely DIO resistant when fed a cholesterol-rich lard-based high-fat diet, whereas on a cholesterol-free palm oil-based high-fat diet, DIO was independent of gut microbiota. In GF lard-fed mice, DIO resistance was conveyed by increased energy expenditure, preferential carbohydrate oxidation, and increased fecal fat and energy excretion. Cecal metabolite profiling revealed a shift in bile acid and steroid metabolites in these lean mice, with a significant rise in 17β-estradiol, which is known to stimulate energy expenditure and interfere with bile acid metabolism. Decreased cecal bile acid levels were associated with decreased hepatic expression of genes involved in bile acid synthesis. These metabolic adaptations were largely attenuated in GF mice fed the palm-oil based high-fat diet. We propose that an interaction of gut microbiota and cholesterol metabolism is essential for fat accretion in normal SPF mice fed cholesterol-rich lard as the main dietary fat source. This is supported by a positive correlation between bile acid levels and specific bacteria of the order Clostridiales (phylum Firmicutes) as a characteristic feature of normal SPF mice fed lard.

          Conclusions

          In conclusion, our study identified dietary cholesterol as a candidate ingredient affecting the crosstalk between gut microbiota and host metabolism.

          Highlights

          • Cholesterol-based but not plant sterol-based high-fat diet protects germfree (GF) mice from diet-induced obesity (DIO).

          • DIO resistant GF mice show preferential carbohydrate oxidation, higher energy expenditure and energy and fat excretion.

          • DIO resistance in GF mice is accompanied by increased steroid hormone levels but decreased bile acid levels in the cecum.

          • Substrate oxidation and fat excretion in DIO resistant GF mice is linked to decreased hepatic Cyp7a1 and Nr1h4 expression.

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          Most cited references40

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          High Fat Diet-Induced Gut Microbiota Exacerbates Inflammation and Obesity in Mice via the TLR4 Signaling Pathway

          Background & Aims While it is widely accepted that obesity is associated with low-grade systemic inflammation, the molecular origin of the inflammation remains unknown. Here, we investigated the effect of endotoxin-induced inflammation via TLR4 signaling pathway at both systemic and intestinal levels in response to a high-fat diet. Methods C57BL/6J and TLR4-deficient C57BL/10ScNJ mice were maintained on a low-fat (10 kcal % fat) diet (LFD) or a high–fat (60 kcal % fat) diet (HFD) for 8 weeks. Results HFD induced macrophage infiltration and inflammation in the adipose tissue, as well as an increase in the circulating proinflammatory cytokines. HFD increased both plasma and fecal endotoxin levels and resulted in dysregulation of the gut microbiota by increasing the Firmicutes to Bacteriodetes ratio. HFD induced the growth of Enterobecteriaceae and the production of endotoxin in vitro. Furthermore, HFD induced colonic inflammation, including the increased expression of proinflammatory cytokines, the induction of Toll-like receptor 4 (TLR4), iNOS, COX-2, and the activation of NF-κB in the colon. HFD reduced the expression of tight junction-associated proteins claudin-1 and occludin in the colon. HFD mice demonstrated higher levels of Akt and FOXO3 phosphorylation in the colon compared to the LFD mice. While the body weight of HFD-fed mice was significantly increased in both TLR4-deficient and wild type mice, the epididymal fat weight and plasma endotoxin level of HFD-fed TLR4-deficient mice were 69% and 18% of HFD-fed wild type mice, respectively. Furthermore, HFD did not increase the proinflammatory cytokine levels in TLR4-deficient mice. Conclusions HFD induces inflammation by increasing endotoxin levels in the intestinal lumen as well as in the plasma by altering the gut microbiota composition and increasing its intestinal permeability through the induction of TLR4, thereby accelerating obesity.
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            Changes in energy expenditure resulting from altered body weight.

            No current treatment for obesity reliably sustains weight loss, perhaps because compensatory metabolic processes resist the maintenance of the altered body weight. We examined the effects of experimental perturbations of body weight on energy expenditure to determine whether they lead to metabolic changes and whether obese subjects and those who have never been obese respond similarly. We repeatedly measured 24-hour total energy expenditure, resting and nonresting energy expenditure, and the thermic effect of feeding in 18 obese subjects and 23 subjects who had never been obese. The subjects were studied at their usual body weight and after losing 10 to 20 percent of their body weight by underfeeding or gaining 10 percent by overfeeding. Maintenance of a body weight at a level 10 percent or more below the initial weight was associated with a mean (+/- SD) reduction in total energy expenditure of 6 +/- 3 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 5 kcal per kilogram per day in the obese subjects (P < 0.001). Resting energy expenditure and nonresting energy expenditure each decreased 3 to 4 kcal per kilogram of fat-free mass per day in both groups of subjects. Maintenance of body weight at a level 10 percent above the usual weight was associated with an increase in total energy expenditure of 9 +/- 7 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 4 kcal per kilogram per day in the obese subjects (P < 0.001). The thermic effect of feeding and nonresting energy expenditure increased by approximately 1 to 2 and 8 to 9 kcal per kilogram of fat-free mass per day, respectively, after weight gain. These changes in energy expenditure were not related to the degree of adiposity or the sex of the subjects. Maintenance of a reduced or elevated body weight is associated with compensatory changes in energy expenditure, which oppose the maintenance of a body weight that is different from the usual weight. These compensatory changes may account for the poor long-term efficacy of treatments for obesity.
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              Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice.

              Obesity is a highly heritable disease driven by complex interactions between genetic and environmental factors. Human genome-wide association studies (GWAS) have identified a number of loci contributing to obesity; however, a major limitation of these studies is the inability to assess environmental interactions common to obesity. Using a systems genetics approach, we measured obesity traits, global gene expression, and gut microbiota composition in response to a high-fat/high-sucrose (HF/HS) diet of more than 100 inbred strains of mice. Here we show that HF/HS feeding promotes robust, strain-specific changes in obesity that are not accounted for by food intake and provide evidence for a genetically determined set point for obesity. GWAS analysis identified 11 genome-wide significant loci associated with obesity traits, several of which overlap with loci identified in human studies. We also show strong relationships between genotype and gut microbiota plasticity during HF/HS feeding and identify gut microbial phylotypes associated with obesity. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Mol Metab
                Mol Metab
                Molecular Metabolism
                Elsevier
                2212-8778
                13 October 2016
                December 2016
                13 October 2016
                : 5
                : 12
                : 1162-1174
                Affiliations
                [1 ]ZIEL – Institute for Food and Health, Technical University of Munich, Gregor-Mendel-Str. 2, 85354 Freising, Germany
                [2 ]Chair of Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, EKFZ – Else Kröner-Fresenius-Center for Nutritional Medicine, Gregor-Mendel-Str. 2, 85354 Freising, Germany
                [3 ]Research Unit Analytical BioGeoChemistry, Department of Environmental Sciences, Helmholtz Zentrum München, Ingolstädter Landstr.1, 85764 Neuherberg, Germany
                [4 ]Chair of Nutritional Physiology, Technical University of Munich, TUM School of Life Sciences Weihenstephan, Gregor-Mendel-Str. 2, 85354 Freising, Germany
                [5 ]Chair of Nutrition and Immunology, Technical University of Munich, TUM School of Life Sciences Weihenstephan, Maximus-von-Imhof-Forum 2, 85354 Freising, Germany
                [6 ]Chair of General Food Technology, Technische Universität München, Alte Akademie 10, 85354 Freising, Germany
                [7 ]Chair of Analytical Food Chemistry, Technische Universität München, Alte Akademie 10, 85354 Freising, Germany
                Author notes
                []Corresponding author. Chair of Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, EKFZ – Else Kröner-Fresenius-Center for Nutritional Medicine, Gregor-Mendel-Str. 2, 85354 Freising, Germany. Fax: +49 8161 71 2404.Chair of Molecular Nutritional MedicineTechnical University of MunichTUM School of Life Sciences WeihenstephanEKFZ – Else Kröner-Fresenius-Center for Nutritional MedicineGregor-Mendel-Str. 2Freising85354Germany mk@ 123456tum.de
                [8]

                Current address: Department for Vascular and Endovascular Surgery, Technical University of Munich, Ismaningerstraβe 22, 81675 München, Germany.

                Article
                S2212-8778(16)30189-2
                10.1016/j.molmet.2016.10.001
                5123202
                27900259
                93ef443b-a40a-4a30-aebd-359bbd3985d8
                © 2016 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 7 September 2016
                : 26 September 2016
                : 4 October 2016
                Categories
                Original Article

                germfree,energy balance,diet-induced obesity resistance,high-fat diet,abcg5, atp-binding cassette sub-family g member 5,abcg8, atp-binding cassette sub-family g member 8,actb, beta actin,akr1d1, aldo-keto-reductase family member 1,anova, analysis of variance,bmr, basal metabolic rate,cd, control diet,ca, cholic acid,cdca, chenodeoxycholic acid,cidea, cell death inducing dffa-like effector,cox4, cytochrome c oxidase subunit 4,cyp7a1, cholesterol 7 alpha-hydroxylase,cyp27a1, cholesterol 27 alpha-hydroxylase,dca, deoxycholic acid,dhcr7, 7-dehydrocholesterol reductase,dio, diet-induced obesity,dee, daily energy expenditure,eef2, eukaryotic elongation factor 2,ft-icr-ms, fourier transform-ion cyclotron resonance-mass spectrometry,ft-ir, fourier transform-infrared spectroscopy,gf, germfree,gusb, beta-glucuronidase,hdca, hyodeoxycholic acid,hmgcr, 3-hydroxy-3-methylglutaryl coenzyme a reductase,hmgcs, 3-hydroxy-3-methylglutaryl coenzyme a synthase 1,hp, heat production,hprt1, hypoxanthine guanine phosphoribosyl transferase,hsd11b1, hydroxysteroid (11-β) dehydrogenase 1,hsp90, heat shock protein 90,ldlr, low density lipoprotein receptor,lhfd, high-fat diet based on lard,mca, muricholic acid,nr1h2, nuclear receptor subfamily 1, group h, member 2 (liver x receptor β),nr1h3, nuclear receptor subfamily 1, group h, member 3 (liver x receptor α),nr1h4, nuclear receptor subfamily 1, group h, member 4 (farnesoid x receptor α),phfd, high-fat diet based on palm oil,prdm16, pr domain containing 16,qpcr, quantitative real-time polymerase chain reaction,spf, specific pathogen free,srebf1, sterol regulatory element binding transcription factor 1,tca, taurocholic acid,tf2b, transcription factor ii b,tmca, tauromuricholic acid,ucp1, uncoupling protein 1,udca, ursodeoxycholic acid,uplc-tof-ms, ultraperformance liquid chromatography-time of flight-mass spectrometry
                germfree, energy balance, diet-induced obesity resistance, high-fat diet, abcg5, atp-binding cassette sub-family g member 5, abcg8, atp-binding cassette sub-family g member 8, actb, beta actin, akr1d1, aldo-keto-reductase family member 1, anova, analysis of variance, bmr, basal metabolic rate, cd, control diet, ca, cholic acid, cdca, chenodeoxycholic acid, cidea, cell death inducing dffa-like effector, cox4, cytochrome c oxidase subunit 4, cyp7a1, cholesterol 7 alpha-hydroxylase, cyp27a1, cholesterol 27 alpha-hydroxylase, dca, deoxycholic acid, dhcr7, 7-dehydrocholesterol reductase, dio, diet-induced obesity, dee, daily energy expenditure, eef2, eukaryotic elongation factor 2, ft-icr-ms, fourier transform-ion cyclotron resonance-mass spectrometry, ft-ir, fourier transform-infrared spectroscopy, gf, germfree, gusb, beta-glucuronidase, hdca, hyodeoxycholic acid, hmgcr, 3-hydroxy-3-methylglutaryl coenzyme a reductase, hmgcs, 3-hydroxy-3-methylglutaryl coenzyme a synthase 1, hp, heat production, hprt1, hypoxanthine guanine phosphoribosyl transferase, hsd11b1, hydroxysteroid (11-β) dehydrogenase 1, hsp90, heat shock protein 90, ldlr, low density lipoprotein receptor, lhfd, high-fat diet based on lard, mca, muricholic acid, nr1h2, nuclear receptor subfamily 1, group h, member 2 (liver x receptor β), nr1h3, nuclear receptor subfamily 1, group h, member 3 (liver x receptor α), nr1h4, nuclear receptor subfamily 1, group h, member 4 (farnesoid x receptor α), phfd, high-fat diet based on palm oil, prdm16, pr domain containing 16, qpcr, quantitative real-time polymerase chain reaction, spf, specific pathogen free, srebf1, sterol regulatory element binding transcription factor 1, tca, taurocholic acid, tf2b, transcription factor ii b, tmca, tauromuricholic acid, ucp1, uncoupling protein 1, udca, ursodeoxycholic acid, uplc-tof-ms, ultraperformance liquid chromatography-time of flight-mass spectrometry

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