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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]
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“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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BackgroundThe microbiota–gut–brain axis in gastrointestinal disorders: stressed bugs, stressed brain or both?
Palma, G. D., Collins, S. M., Berčík, P., & Verdu, E. F. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2014.273995 · Cited by 309
“Moreover, germ-free mice have an impaired capacity to harvest energy from the diet (Wostmann, 1981) and are protected against diet-induced obesity (Bäckhed et al. 2007; Rabot et al. 2010).”
BackgroundHuman gut microbiota: the links with dementia development
Alkasir, R., Li, J., Li, X., Jin, M., & Zhu, B. (2016) · Protein & Cell · doi:10.1007/s13238-016-0338-6 · Cited by 289
The Intestinal Microbiota in Metabolic Disease
Woting, A., & Blaut, M. (2016) · Nutrients · doi:10.3390/nu8040202 · Cited by 284
“Indeed, experiments by Rabot et al. (2010) are in conflict with this explanation because they showed that the intestinal microbiota promotes lipid absorption: High-fat diet-fed conventional mice excreted 40% less lipids in their feces than high-fat diet-fed germfree mice [29], the opposite of what…”
BackgroundResultInfluentialGut Microbiota Is a Key Modulator of Insulin Resistance in TLR 2 Knockout Mice
Caricilli, A. M., Picardi, P. K., de Abreu, L. L., Ueno, M., Prada, P. O., Ropelle, E. R., Hirabara, S. M., Castoldi, Â., Moraes‐Vieira, P. M., Câmara, N. O. S., et al. (2011) · PLoS Biology · doi:10.1371/journal.pbio.1001212 · Cited by 285
RetractedGeurts, L., Neyrinck, A. M., Delzenne, N. M., Knauf, C., & Cani, P. D. (2013) · Beneficial Microbes · doi:10.3920/bm2012.0065 · Cited by 287
“I P A dd re ss :1 30 .1 04 .1 94 .2 24 Beneficial Microbes 5(1) 5 and insulin resistance induced by a high-fat diet (Backhed et al., 2007; Ding et al., 2010; Rabot et al., 2010).”
BackgroundMicrobial modulation of insulin sensitivity
Khan, M. T., Nieuwdorp, M., & Bäckhed, F. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.07.006 · Cited by 260
Is the Gut Microbiota a New Factor Contributing to Obesity and Its Metabolic Disorders?
Harris, K. A., Kassis, A. N., Major, G. C., & Chou, C. J. (2012) · Journal of Obesity · doi:10.1155/2012/879151 · Cited by 289
“To further examine if glucose tolerance of mice is affected by the presence or absence of the gut microbiota, we fed both GF and Conv C57BL/6J mice with a high-fat diet, and our results showed that GF mice did not develop diet-induced obesity and glucose intolerance [36].”
BackgroundSelf-citationThe Role of Gut Microbiota on Insulin Resistance
Caricilli, A. M., & Saad, M. A. (2013) · Nutrients · doi:10.3390/nu5030829 · Cited by 285
“against related comorbidities [55,110] (Figure 2).”
Western diets, gut dysbiosis, and metabolic diseases: Are they linked?
Martinez, K., Leone, V., & Chang, E. B. (2017) · Gut Microbes · doi:10.1080/19490976.2016.1270811 · Cited by 291
“For example, several groups have shown that germ-free mice fed a high-fat, high-sugar diet are resistance to diet-induced obesity (DIO).(5,8) Transplant of microbes induced by Western diets or obesity result in an increase in fat mass in germ-free mouse recipients.”
BackgroundThe Mouse Microbiome Is Required for Sex-Specific Diurnal Rhythms of Gene Expression and Metabolism
Weger, B. D., Gobet, C., Yeung, J., Martin, E., Jimenez, S., Betrisey, B., Foata, F., Berger, B., Balvay, A., Foussier, A., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2018.09.023 · Cited by 269
“The male-biased concentration correlated with male-biased mRNA expression of the folate transporter SLC19A1 (RFC1) and the key enzyme for purine metabolism MTHFD2 (methylenetetrahydrofolate dehydrogenase and cyclohydrolase) (Ben-Sahra et al., 2016).”
BackgroundMethodInfluentialSelf-citationIs butyrate the link between diet, intestinal microbiota and obesity-related metabolic diseases?
Brahe, L. K., Astrup, A., & Larsen, L. H. (2013) · Obesity Reviews · doi:10.1111/obr.12068 · Cited by 264
“Moreover, it has been suggested that germ-free animals are protected from pro-inflammatory consequences of a high-fat diet (113), supporting a key role for the intestinal microbiota in the metabolic response to the diet.”
BackgroundDoes lipopolysaccharide-mediated inflammation have a role in OA?
Huang, Z., & Kraus, V. B. (2015) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2015.158 · Cited by 265
The Alterations in and the Role of the Th17/Treg Balance in Metabolic Diseases
Zhang, S., Gang, X., Yang, S., Cui, M., Sun, L., Li, Z., & Wang, G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.678355 · Cited by 263
Non-alcoholic steatohepatitis: pathogenesis and novel therapeutic approaches
Schuppan, D., & Schattenberg, J. M. (2013) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.12212 · Cited by 256
Programming of Host Metabolism by the Gut Microbiota
Bäckhed, F. (2011) · Annals of Nutrition and Metabolism · doi:10.1159/000328042 · Cited by 267
“AMPK (AMP-activated protein kinase) is an important energy sensor in all organisms from yeast to mammals and promotes energy-generating pathways, while shutting off anabolic pathways [ , , , , ,”
BackgroundResveratrol, Metabolic Syndrome, and Gut Microbiota
Chaplin, A. M. L., Carpéné, C., & Mercader, J. (2018) · Nutrients · doi:10.3390/nu10111651 · Cited by 256
“Since then, numerous studies have shown that the gut microbiota composition in obesity is different compared to lean subjects, characterized by increased levels of Firmicutes and less Bacteroidetes [177,178], increased capacity in energy harvesting from dietary polysaccharides [175,179], and is associated with increas…”
BackgroundNon-alcoholic fatty liver and the gut microbiota
Bashiardes, S., Shapiro, H., Rozin, S., Shibolet, O., & Elinav, E. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.06.003 · Cited by 241
“The prevalence of NAFLD is greatly increased in patients suffering from other pre-existing manifestations of the metabolic syndrome, such as obesity, type 2 diabetes, hyperlipidemia, and hypertension [1].”
BackgroundThe critical role of gut microbiota in obesity
Cheng, Z., Zhang, L., Yang, L., & Chu, H. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1025706 · Cited by 233
Livshits, G., & Kalinkovich, A. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100980 · Cited by 245
Oral–Gut Microbiome Axis in Gastrointestinal Disease and Cancer
Park, S.-Y., Hwang, B.-O., Lim, M., Ok, S.-H., Lee, S., Chun, K., Park, K.-K., Hu, Y., Chung, W., & Song, N. (2021) · Cancers · doi:10.3390/cancers13092124 · Cited by 247
MECHANISMS IN ENDOCRINOLOGY: Gut microbiota in patients with type 2 diabetes mellitus
Allin, K. H., Nielsen, T., & Pedersen, O. B. (2014) · European Journal of Endocrinology · doi:10.1530/eje-14-0874 · Cited by 243
Fecal microbiota transplantation broadening its application beyond intestinal disorders
Xu, M.-Q. (2015) · World Journal of Gastroenterology · doi:10.3748/wjg.v21.i1.102 · Cited by 231
van der Beek, C. M., Canfora, E. E., Kip, A. M., Gorissen, S. H. M., Damink, S. W. M. O., van Eijk, H. M. H., Holst, J. J., Blaak, E. E., Dejong, C. H. C., & Lenaerts, K. (2018) · Metabolism · doi:10.1016/j.metabol.2018.06.009 · Cited by 238
Spiljar, M., Merkler, D., & Trajkovski, M. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01353 · Cited by 219
Impact of Gut Microbiota and Microbiota-Related Metabolites on Hyperlipidemia
Jia, X., Xu, W., Zhang, L., Li, X., Wang, R., & Wu, S. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.634780 · Cited by 237
“When fed with high-fat, high-carbohydrate Western diet, GF mice have less hypercholesterolemia and more cholesterol excretion in the liver and feces (Rabot et al., 2010).”
BackgroundClostridium ramosum Promotes High-Fat Diet-Induced Obesity in Gnotobiotic Mouse Models
Woting, A., Pfeiffer, N., Loh, G., Klaus, S., & Blaut, M. (2014) · mBio · doi:10.1128/mbio.01530-14 · Cited by 224
“A study comparing conventional and germfree mice revealed that the intestinal microbiota increases intestinal absorption of lipids, resulting in better food efficiency and marked obesity (33).”
BackgroundFortification and Health: Challenges and Opportunities
Dwyer, J. T., Wiemer, K. L., Dary, O., Keen, C. L., King, J. C., Miller, K. B., Philbert, M. A., Tarasuk, V. S., Taylor, C. L., Gaine, P. C., et al. (2015) · Advances in Nutrition · doi:10.3945/an.114.007443 · Cited by 237
Lam, Y. Y., Ha, C. W. Y., Hoffmann, J. M. A., Oscarsson, J., Dinudom, A., Mather, T. J., Cook, D. I., Hunt, N. H., Caterson, I. D., Holmes, A. J., et al. (2015) · Obesity · doi:10.1002/oby.21122 · Cited by 223
“There is evidence for causal relationships between diet, gut dysfunction, and deleterious metabolic sequelae: high-fat diets induced inflammation and increased gut permeability (3,4); antibiotics normalized metabolic parameters in diet-induced obese mice (4); germ-free mice were protected against diet-induced obesity…”
BackgroundRecent advances in the development of farnesoid X receptor agonists.
Ali, A. H., Carey, E. J., & Lindor, K. D. (2015) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2305-5839.2014.12.06 · Cited by 224
“Other factors are activation of toll-like receptor 4 (TLR4) by intestinal bacterial lipopolysaccharide (67-69) and other pro-inflammatory signals produced by dysbiosis (gut microbiota imbalance) (70-72).”
BackgroundThe Role of Gut Microbiota on Cholesterol Metabolism in Atherosclerosis
Vourakis, M., Mayer, G., & Rousseau, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158074 · Cited by 233
The intestinal microbiota regulates host cholesterol homeostasis
Roy, T. L., Lécuyer, E., Chassaing, B., Rhimi, M., Lhomme, M., Boudebbouze, S., Ichou, F., Barceló, J. H., Huby, T., Guérin, M., et al. (2019) · BMC Biology · doi:10.1186/s12915-019-0715-8 · Cited by 223
“mice [24] but discrepant with others [22].”
BackgroundSelf-citationDietary fat and gut microbiota interactions determine diet-induced obesity in mice
Kübeck, R., Bonet-Ripoll, C., Hoffmann, C., Walker, A., Müller, V. M., Schüppel, V. L., Lagkouvardos, I., Scholz, B., Engel, K.-H., Daniel, H., et al. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.10.001 · Cited by 211
Schéle, E., Grahnemo, L., Anesten, F., Hallén, A., Bäckhed, F., & Jansson, J.-O. (2013) · Endocrinology · doi:10.1210/en.2012-2151 · Cited by 209
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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