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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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“HFD‑fed germ‑free mice gained less weight than HFD‑fed conventional mice [29], indicating that HFD itself is insufficient to induce MAFLD.”
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Maternal Microbiota Transfer Programs Offspring Eating Behavior
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Intestinal microbiota has important effect on severity of hand foot and mouth disease in children
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“Interest in intestinal microbiota functions has grown recently, including those related to metabolism [36], the immune system [15], and even the central nervous system [37, 38].”
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“Compared with conventionally raised mice, HFD-induced obesity, insulin resistance, hepatic steatosis, and dyslipidemia were attenuated in germ-free mice [81, 82].”
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Microbiota–Liver Diseases Interactions
Capparelli, R., Cuomo, P., Gentile, A., & Iannelli, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043883 · Cited by 12
“Germ-free mice, in fact, are characterized by the higher expression level of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene (HMGCR)—involved in cholesterol biosynthesis—and up-regulation of membrane transporters for cholesterol excretion in the liver and small intestine [46].”
BackgroundHarnessing the beneficial properties of adipogenic microbes for improving human health
Dhurandhar, N. V., Geurts, L., Atkinson, R. L., Casteilla, L., Clément, K., Gérard, P., Vijay‐Kumar, M., Nam, J. H., Nieuwdorp, M., Trovato, G. M., et al. (2013) · Obesity Reviews · doi:10.1111/obr.12045 · Cited by 13
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“Compared to conventionally raised mice on a chow diet, germ-free mice had comparable plasma high-density lipoprotein cholesterol (HDL-C) and lower serum low-density lipoprotein cholesterol (LDL-C) concentrations (Velagapudi et al., 2010), while germ-free mice on a high-fat diet had lower serum HDL-C and total choleste…”
Consumption of salt leads to ameliorate symptoms of metabolic disorder and change of gut microbiota
Do, M. H., Lee, H., Oh, M., Jhun, H., Ha, S. K., & Park, H. (2020) · European Journal of Nutrition · doi:10.1007/s00394-020-02209-0 · Cited by 12
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Complex interplay of gut microbiota between obesity and asthma in children
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The role of the gut microbial metabolism of sterols and bile acids in human health
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Gustafson, K. L., Busi, S. B., McAdams, Z. L., McCorkle, R. E., Khodakivskyi, P., Bivens, N. J., Davis, D. J., Raju, M., Coghill, L. M., Goun, E. A., et al. (2025) · Microbiome · doi:10.1186/s40168-025-02226-3 · Cited by 12
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Lequoy, M., Gigante, E., Couty, J., & Desbois‐Mouthon, C. (2020) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2019-0044 · Cited by 12
“Germ-free (GF) C57BL/6J mice gain less weight and do not develop steatosis and insulin resistance when given an HFD compared to conventionalized mice [106], [107].”
BackgroundAmoxicillin Impact on Pathophysiology Induced by Short Term High Salt Diet in Mice
Kumar, S., Nagarajan, P., Yadav, P. K., Pandey, R. P., Chang, C.-M., & Raj, V. S. (2022) · Scientific Reports · doi:10.1038/s41598-022-21270-9 · Cited by 11
The disposition of polychlorinated biphenyls (PCBs) differs between germ-free and conventional mice
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Contribution of the gut microbiota to the pathogenesis of insulin resistance (literature review)
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Decoding the general role of tRNA queuosine modification in eukaryotes
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Vaccine therapy for dysbiosis-related diseases
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The Gut Microbiota and Effects on Metabolism
Hussey, S. E., & Bergman, M. A. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-386456-7.02009-8 · Cited by 8
Gut microbiota in patients with type 2 diabetes mellitus
Allin, K. H., Nielsen, T., & Pedersen, O. B. (2015) · Cited by 8
Alternatives to Insulin for the Regulation of Blood Sugar Levels in Type 2 Diabetes
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“Germ-free mice without intestinal bacteria do not develop insulin resistance or weight gain when fed a high-carbohydrate high-fat diet [61].”
BackgroundDual Regulation Mechanism of Obesity: DNA Methylation and Intestinal Flora
Ren, Y., Huang, P., Zhang, L., Tang, Y.-F., Luo, S., She, Z., Peng, H., Chen, Y.-Q., Luo, J., Duan, W.-X., et al. (2024) · Biomedicines · doi:10.3390/biomedicines12081633 · Cited by 8
“Compared with conventional mice, the digestion and absorption capacity of germ-free (GF) mice fed a high-fat diet was reduced, resulting in an increase in 24 h fecal volume and calorific content in feces [141,142].”
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Host—microbial interactions in metabolic diseases: from diet to immunity
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“of GF mice, an increase in phosphorylated AMP-activated protein kinase (AMPK) level leads to enhanced fatty acid oxidation in peripheral tissues (Bäckhed et al., 2007; Rabot et al., 2010).”
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“Some studies showed that microorganisms could act as regulators of lipid digestion, absorption, storage and secretion in the gastrointestinal tract [90–92], which indicated that their synergistic action with the host could hydrolyze lipid substances more efficiently, which was conducive to the…”
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“For example, compared to conventional mice, germ-free mice fed with a high fat diet showed an increase in fecal lipid levels (Rabot et al., 2010).”
BackgroundThe role of gut microbiota in metabolic regulation
Кравчук, Е. Н., Неймарк, А. Е., Grineva, E. N., & Galagudza, M. M. (2016) · Diabetes Mellitus · doi:10.14341/dm7704 · Cited by 6
Gut microbiota: a new risk factor for atherosclerosis?
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“Germ-free mice weigh less than age-matched conventionally housed mice, have reduced visceral adiposity [6,7], and are partially resistant to diet-induced obesity and metabolic dysfunction [8,9].”
BackgroundLe microbiote intestinal: composition et fonctions
Gérard, P. (2011) · Phytothérapie · doi:10.1007/s10298-011-0615-8 · Cited by 6
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Sex Differences in Fish Oil and Olanzapine Effects on Gut Microbiota in Diet-Induced Obese Mice
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IL-25 Treatment Improves Metabolic Syndrome in High-Fat Diet and Genetic Models of Obesity
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“fed a HFD via the induction and maintenance of eosinophils in visceral adipose tissue.(40) In addition, IL-25”
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Ciarambino, T., Crispino, P., Leto, G., Minervini, G., Para, O., & Giordano, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241210409 · Cited by 4
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“Recent studies showed, for example, that germ-free mice are resistant to obesity when consuming a high-fat, high-carbohydrate Western diet (Rabot et al., 2010).”
Background
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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