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Germ‐free C57BL/6J mice are resistant to high‐fat‐diet‐induced insulin resistance and have altered cholesterol metabolism
Abstract
Recent studies showed that germ‐free (GF) mice are resistant to obesity when consuming a high‐fat, high‐carbohydrate Western diet. However, it remains unclear what mechanisms are involved in the antiobesity phenotype and whether GF mice develop insulin resistance and dyslipidemia with high‐fat (HF) feeding. In the present study, we compared the metabolic consequences of HF feeding on GF and conventional (conv) C57BL/6J mice. GFmice consumed fewer calories, excreted more fecal lipids, and weighed significantly less than conv mice. GF/HF animals also showed enhanced insulin sensitivity with improved glucose tolerance, reduced fasting and nonfasting insuline‐mia, and increased phospho‐Akt (Ser‐473) in adipose tissue. In association with enhanced insulin sensitivity, GF/HF mice had reduced plasma TNF‐α and total serum amyloid A concentrations. Reduced hypercholes‐terolemia, a moderate accretion of hepatic cholesterol, and an increase in fecal cholesterol excretion suggest an altered cholesterol metabolism in GF/HF mice. Pronounced nucleus SREBP2 proteins and up‐regulation of cholesterol biosynthesis genes indicate that enhanced cholesterol biosynthesis contributed to the cholesterol homeostasis in GF/HF mice. Our results demonstrate that fewer calorie consumption and increased lipid excretion contributed to the obesity‐resistant phenotype of GF/HF mice and reveal that insulin sensitivity and cholesterol metabolism are metabolic targets influenced by the gut microbiota.— Rabot, S., Membrez, M., Bruneau, A., Gerard, P., Harach, T., Moser, M., Raymond, F., Mansourian, R., Chou. C. J. Germ‐free C57BL/6J mice are resistant to high‐fat‐diet‐induced insulin resistance and have altered cholesterol metabolism. FASEB J. 24, 4948–4959 (2010). www.fasebj.org
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“germ-free mice are resistant to the obesogenic effects of high-fat diets243”
From Comorbidity between major depressive disorder and physical diseases: a comprehensive review of epidemiology, mechanisms and management (2023) · cites this paper as [243]
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“Germ-free (GF) mice are protected from the metabolic consequences of high-fat diets, suggesting that gut microbes may be important mediators of lipid-induced metabolic dysfunction (28).”
From The gut microbiota at the intersection of diet and human health (2018) · cites this paper as [28]
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“The gut microbiota has been shown to affect lipid metabolism and lipid levels in blood and tissues, both in mice and humans.”
From Dietary lipids, gut microbiota and lipid metabolism (2019) · cites this paper as [31]
In the citing paper
“In contrast, circulating triglycerides, HDL, and total cholesterol levels are increased by the gut microbiota in mice on a high-fat diet [31].”
From Dietary lipids, gut microbiota and lipid metabolism (2019) · cites this paper as [31]
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“03% from cholesterol) for 11 weeks weighed less, consumed less calories, excreted more fecal lipids and had improved insulin sensitivity and glucose tolerance compared to conventionally raised, high-fat-fed cohorts [24].”
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“Investigations on the infl uence of the nutrition on obesity in germfree and conventional mice revealed that germfree mice display reduced food intake and are resistant to diet-induced obesity [71, 72].”
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“The source of this LPS is likely from gut microorganisms which dynamically respond to diet and are known to contribute to weight and metabolic regulation (Manco et al., 2010; Rabot et al., 2010; Tilg and Kaser, 2011).”
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“Finally, germ-free mice were also reported to be resistant to high-fat diet (HFD)-induced IR, showing enhanced hepatic and adipose tissue insulin sensitivity and fecal lipid excretion [41], revealing that insulin resistance index (HOMA-IR) is transmissible [38].”
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The Role of Lipids in the Regulation of Immune Responses
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Lentil (Lens culinaris L.): A prebiotic-rich whole food legume
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Probiotics, prebiotics, and the host microbiome: the science of translation
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High fat diet drives obesity regardless the composition of gut microbiota in mice
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“Early work led by us and others showed that germfree mice remain lean and glucose tolerant on a HF diet 18,19 .”
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“The possible mechanism involved might be (1) degradation of indigestible polysaccharide by GM increasing hepatic lipogenesis in the host and (2) suppressing intestinal expression of angiopoietin-like 4 (ANGPTL4), the inhibitor of lipoprotein lipase (LPL) thereby blocking the fatty acid metabolism leading to increased…”
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Mfge8 promotes obesity by mediating the uptake of dietary fats and serum fatty acids
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“Carbohydrate metabolism One of the most striking metabolic phenotypes of germ-free mice is their profoundly blunted serum glucose response to carbohydrate intake [36].”
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“By contrast, when fed a high-fat diet, germ-free mice are less prone to obesity as compared with their conventionally raised counterparts (Rabot et al., 2010).”
Reichardt, F., Chassaing, B., Nezami, B. G., Li, G., Tabatabavakili, S., Mwangi, S. M., Uppal, K., Liang, B., Vijay–Kumar, M., Jones, D. P., et al. (2016) · The Journal of Physiology · doi:10.1113/jp273269 · Cited by 109
“Finally, we characterized metabolites related to WD consumption such as palmitate and triglycerides, and similar increases in feces have been already reported not only in HFD-fed WT mice, but also GF mice (Rabot et al., 2010).”
Sheng, Y., Ren, H., Limbu, S. M., Sun, Y., Qiao, F., Zhai, W., Du, Z., & Zhang, M. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.01124 · Cited by 111
“Compared to conventional mice, germ-free C57BL/6J mice gained less weight and accumulated less fat pad when fed a chow or HFD (Backhed et al., 2004; Rabot et al., 2010).”
BackgroundThe Gut Microbiome and Individual-Specific Responses to Diet
Leshem, A., Segal, E., & Elinav, E. (2020) · mSystems · doi:10.1128/msystems.00665-20 · Cited by 109
“…were previously reported to be resilient to deleterious effects of high-fat diet (HFD) feeding, such as weight gain and glucose intolerance (45, 46); however, findings from recent studies using various types of HFDs suggest that vivarium-dependent factors may differentially induce this trait…”
ResultOsteoarthritis induced by destabilization of the medial meniscus is reduced in germ-free mice
Ulici, V., Kelley, K. L., Azcárate-Peril, M. A., Cleveland, R. J., Sartor, R. B., Schwartz, T. A., & Loeser, R. F. (2018) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2018.05.016 · Cited by 113
Kotsiliti, E., Leone, V., Schuehle, S., Govaere, O., Li, H., Wolf, M. J., Horvatic, H., Bierwirth, S., Hundertmark, J., Inverso, D., et al. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.04.037 · Cited by 108
Kasahara, K., Tanoue, T., Yamashita, T., Yodoi, K., Matsumoto, T., Emoto, T., Mizoguchi, T., Hayashi, T., Kitano, N., Sasaki, N., et al. (2017) · Journal of Lipid Research · doi:10.1194/jlr.m072165 · Cited by 105
The Gut Microbiota Regulates Endocrine Vitamin D Metabolism through Fibroblast Growth Factor 23
Bora, S. A., Kennett, M. J., Smith, P. B. W., Patterson, A. D., & Cantorna, M. T. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00408 · Cited by 110
Chen, W., Wen, L., Bao, Y., Tang, Z., Zhao, J., Zhang, X., Wei, T., Zhang, J., Ma, T., Zhang, Q., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2203894119 · Cited by 111
“Among them, cholesterol metabolism is regulated by the gut microbiota (8, 9), and its homeostasis is inextri-cably bound with liver cancer (3).”
Nutritional modulation of gut microbiota — the impact on metabolic disease pathophysiology
Ojeda, P., Bobe, A. M., Dolan, K. T., Leone, V., & Martinez, K. (2015) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2015.08.013 · Cited by 108
“Underlying the role of microbiota in metabolic processes is the finding that high-fat fed GF mice exhibit improved fasting and non-fasting glucose tolerance as well as decreased cholesterol levels compared to conventional counterparts [16].”
BackgroundCholesterol-to-Coprostanol Conversion by the Gut Microbiota: What We Know, Suspect, and Ignore
Juste, C., & Gérard, P. (2021) · Microorganisms · doi:10.3390/microorganisms9091881 · Cited by 112
“Indeed, germ-free mice have an altered cholesterol metabolism [128], and a recent study showed that microbiota depletion using antibiotics leads to increased blood cholesterol in ApoE-deficient mice.”
BackgroundSelf-citationFeatured article: Structure moderation of gut microbiota in liraglutide-treated diabetic male rats
Zhang, Q., Xiao, X., Zheng, J., Li, M., Yu, M., Ping, F., Wang, T., & Wang, X. (2018) · Experimental Biology and Medicine · doi:10.1177/1535370217743765 · Cited by 101
“Transferring the gut microbial community from obese mice to these germ-free mice causes a significant increase in total body fat content.(2,3) Shaping the microbial composition is a potential therapeutic approach in T2D.”
Nakahara, D., Nan, C., Mori, K., Hanayama, M., Kikuchi, H., Hirai, S., & Egashira, Y. (2019) · European Journal of Nutrition · doi:10.1007/s00394-019-02162-7 · Cited by 102
Microbial Metabolites: Critical Regulators in NAFLD
Dai, X., Hou, H., Zhang, W., Liu, T., Li, Y., Wang, S., Wang, B., & Cao, H. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.567654 · Cited by 103
“The germ-free mice were resistant to high-fat diet (HFD)-induced hepatic lipid accumulation compared with the conventionally fed mice (Rabot et al., 2010).”
BackgroundGut microbiota in health and disease: an overview focused on metabolic inflammation
Nagpal, R., Kumar, M., Yadav, A. K., Hemalatha, R., Yadav, H., Marotta, F., & Yamashiro, Y. (2016) · Beneficial Microbes · doi:10.3920/bm2015.0062 · Cited by 97
The effects of commensal microbiota on immune cell subsets and inflammatory responses
Chinen, T., & Rudensky, A. Y. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01083.x · Cited by 99
“strains of GF animals compared to conventional animals (5).”
BackgroundJanssen, A. W. F., Katiraei, S., Bartosinska, B., Eberhard, D., Willems van Dijk, K., & Kersten, S. (2018) · Diabetologia · doi:10.1007/s00125-018-4583-5 · Cited by 96
Importance of Large Intestine in Regulating Bile Acids and Glucagon-Like Peptide-1 in Germ-Free Mice
Selwyn, F. P., Csanaky, I. L., Zhang, Y., & Klaassen, C. D. (2015) · Drug Metabolism and Disposition · doi:10.1124/dmd.115.065276 · Cited by 97
“Germ-free (GF) mice, which lack intestinal bacteria, are resistant to high-fat diet-induced obesity (Backhed et al., 2007; Rabot et al., 2010), and, in contrast, colonization of GF mice with intestinal bacteria results in increased body fat content and insulin resistance (Backhed et al., 2004).”
BackgroundGut Microbial-Derived Short Chain Fatty Acids: Impact on Adipose Tissue Physiology
May, K. S., & den Hartigh, L. J. (2023) · Nutrients · doi:10.3390/nu15020272 · Cited by 100
IL-17 Axis Driven Inflammation in Non-Alcoholic Fatty Liver Disease Progression
Giles, D. A., Moreno‐Fernandez, M. E., & Divanovic, S. (2015) · Current Drug Targets · doi:10.2174/1389450116666150531153627 · Cited by 99
“Further, experimental animal models of diet-induced obesity have shown that the intestinal microbiota are essential for development of obesity [86, 87] and play an important role in regulating NAFLD progression [88].”
BackgroundFecal Microbial Transplantation and Its Potential Application in Cardiometabolic Syndrome
Leshem, A., Horesh, N., & Elinav, E. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01341 · Cited by 96
Diet-gut microbiota interactions on cardiovascular disease
Zhang, X., & Gérard, P. (2022) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2022.03.028 · Cited by 98
“For example, GF mice have an altered cholesterol metabolism [81] and the depletion of gut microbiota in ApoE / mice caused a marked elevation of plasma cholesterol accompanied with larger aortic lesions compared to conventional ApoE / mice [77,78].”
BackgroundSelf-citationInteraction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism
Caesar, R., Nygrén, H., Orešič, M., & Bäckhed, F. (2016) · Journal of Lipid Research · doi:10.1194/jlr.m065847 · Cited by 94
Effects of Consuming Xylitol on Gut Microbiota and Lipid Metabolism in Mice
Uebanso, T., Kano, S., Yoshimoto, A., Naito, C., Shimohata, T., Mawatari, K., & Takahashi, A. (2017) · Nutrients · doi:10.3390/nu9070756 · Cited by 100
“An amount of dietary indigestible fiber and gut microbiota which digest fiber regulates cecum weight [29,30].”
BackgroundGong, M., Wen, S., Nguyen, T., Wang, C., Jin, J., & Zhou, L. (2020) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s232377 · Cited by 95
The Metabolic Role and Therapeutic Potential of the Microbiome
Olofsson, L. E., & Bäckhed, F. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnac004 · Cited by 99
Lau, L. H. S., & Wong, S. H. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-10-8684-7_9 · Cited by 93
Ni, Y., Ni, L., Zhuge, F., Xu, L., Fu, Z., & Ota, T. (2020) · Obesity · doi:10.1002/oby.22674 · Cited by 92
“intestinal microbial transplantation (9,35).”
Developmental Regulation of Drug-Processing Genes in Livers of Germ-Free Mice
Selwyn, F. P., Cheng, S. L., Bammler, T. K., Prasad, B., Vrana, M., Klaassen, C. D., & Cui, J. Y. (2015) · Toxicological Sciences · doi:10.1093/toxsci/kfv110 · Cited by 92
“GF mice are resistant to high-fat diet induced obesity, even though they consume more food, they are more active, excrete more lipids in feces and is more insulin sensitive (Backhed et al., 2007; Rabot et al., 2010).”
BackgroundZhuang, P., Zhang, Y., Shou, Q., Li, H., Zhu, Y., He, L., Chen, J., & Jiao, J. (2020) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201900946 · Cited by 94
Coming full circle in diabetes mellitus: from complications to initiation
Harcourt, B. E., Penfold, S. A., & Forbes, J. M. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.236 · Cited by 91
Chan, K. L., Tam, T. H., Boroumand, P., Prescott, D., Costford, S. R., Escalante, N. K., Fine, N., Tu, Y., Robertson, S. J., Prabaharan, D., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.02.027 · Cited by 88
Age-Related Changes in the Gut Microbiota Modify Brain Lipid Composition
Albouery, M., Buteau, B., Gregoire, S., Cherbuy, C., de Barros, J.-P. P., Martine, L., Chain, F., Cabaret, S., Berdeaux, O., Bron, A. M., et al. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2019.00444 · Cited by 90
“…indicates that the presence of microbes in the gut has an impact on the lipid composition of metabolically important organs such as adipose tissue and liver, but also lipid-rich organs such as the retina (Backhed et al., 2004, 2007; Oresic et al., 2009; Rabot et al., 2010; Velagapudi et al., 2010).”
BackgroundClinical reviews in allergy and immunology
Leung, D. Y. M., Ledford, D. K., Wechsler, M. E., Fulkerson, P. C., Bochner, B. S., Gauvreau, G. M., Gleich, G. J., Henkel, T., Kolbeck, R., Mathur, S. K., et al. (2012) · Cited by 87
Jejunum: The understudied meeting place of dietary lipids and the microbiota
Lema, I., Araújo, J. R., Rolhion, N., & Demignot, S. (2020) · Biochimie · doi:10.1016/j.biochi.2020.09.007 · Cited by 92
The Influence of Nutrition on Intestinal Permeability and the Microbiome in Health and Disease
Inczefi, O., Bacsúr, P., Resál, T., Keresztes, C., & Molnár, T. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.718710 · Cited by 90
Metadata
- Authors
- Rabot, S., Membrez, M., Bruneau, A., Gérard, P., Harach, T., Moser, M., Raymond, F., Mansourian, R., & Chou, C. J.
- Affiliations
- Microbiologie de l’alimentation au service de la santé (FR)
- Department of Nutrition and Health Nestlé Research Center Lausanne Switzerland
- Nestlé (Switzerland) (CH)
- Department of Bioanalytical Science Nestlé Research Center Lausanne Switzerland
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2010-08-19
- Volume
- 24
- Issue
- 12
- Pages
- 4948-4959
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2088697466
- Cited by
- 610
- References
- 41
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 34 · 2023: 43 · 2022: 50 · 2021: 64 · 2020: 75 · 2019: 49 · 2018: 42 · 2017: 40 · 2016: 39 · 2015: 44 · 2014: 24 · 2013: 33 · 2012: 22
- FWCI
- 10.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- germ-free mice, gut microbiota, high-fat diet, insulin resistance, cholesterol metabolism, hypercholesterolemia, obesity resistance, glucose tolerance, TNF-α, serum amyloid A, SREBP2, cholesterol biosynthesis, liver cholesterol, fecal cholesterol excretion, C57BL/6J mice
- MeSH terms
- Animals, Body Weight, Cholesterol, Dietary Fats, Germ-Free Life, Glucose Tolerance Test, Glycogen, Insulin Resistance, Lipids, Liver, Male, Mice, Inbred C57BL, Obesity, Blotting, Western, Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Mice
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