Mechanisms underlying the resistance to diet-induced obesity in germ-free mice
Open accessAbstract
The trillions of microbes that colonize our adult intestines function collectively as a metabolic organ that communicates with, and complements, our own human metabolic apparatus. Given the worldwide epidemic in obesity, there is interest in how interactions between human and microbial metabolomes may affect our energy balance. Here we report that, in contrast to mice with a gut microbiota, germ-free (GF) animals are protected against the obesity that develops after consuming a Western-style, high-fat, sugar-rich diet. Their persistently lean phenotype is associated with increased skeletal muscle and liver levels of phosphorylated AMP-activated protein kinase (AMPK) and its downstream targets involved in fatty acid oxidation (acetylCoA carboxylase; carnitine-palmitoyltransferase). Moreover, GF knockout mice lacking fasting-induced adipose factor (Fiaf), a circulating lipoprotein lipase inhibitor whose expression is normally selectively suppressed in the gut epithelium by the microbiota, are not protected from diet-induced obesity. Although GF Fiaf −/− animals exhibit similar levels of phosphorylated AMPK as their wild-type littermates in liver and gastrocnemius muscle, they have reduced expression of genes encoding the peroxisomal proliferator-activated receptor coactivator (Pgc-1α) and enzymes involved in fatty acid oxidation. Thus, GF animals are protected from diet-induced obesity by two complementary but independent mechanisms that result in increased fatty acid metabolism: ( i ) elevated levels of Fiaf, which induces Pgc-1α; and ( ii ) increased AMPK activity. Together, these findings support the notion that the gut microbiota can influence both sides of the energy balance equation, and underscore the importance of considering our metabolome in a supraorganismal context.
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GF animals and antibiotic treatment result in drastically lower SCFA levels.
“which is supported by the fact that GF animals and antibiotic treatment results in drastically lower SCFA levels (Backhed et al., 2007;Hoverstad and Midtvedt, 1986;Palleja et al., 2018;Zhao et al., 2016).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Backhed et al., 2007
The paper’s introductory discussion of prior work says that colonizing germ-free mice increases fermentation of carbohydrates to SCFAs in the distal gut. That supports the germ-free comparison qualitatively, but the paper gives no SCFA levels or evidence that the difference is drastic, and it does not address antibiotic treatment. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe gut microbiome modulates leptin signaling and adiposity.
“several studies have demonstrated the significant role of gut microbiome in modulating leptin signaling and adiposity.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [580]
Germ-free mice are protected from diet-induced obesity when fed a Western-style diet.
“Germ-free mice are protected from diet-induced obesity when fed a Western-style diet8–10”
From Diet–microbiota interactions as moderators of human metabolism (2016) · cites this paper as [8]
Under a Western-style diet, the gut microbiota regulates obesity through additional pathways.
“Experiments that use a Western-style diet, which is devoid of fibres and rich in calories from saturated fat and sucrose, demonstrate that the gut microbiota regulates obesity through additional pathways8.”
From Diet–microbiota interactions as moderators of human metabolism (2016) · cites this paper as [8]
Germ-free mice are protected from diet-induced obesity when fed high sucrose and lard.
“germ-free mice are protected from diet-induced obesity when fed high levels of sucrose and lard8”
From Diet–microbiota interactions as moderators of human metabolism (2016) · cites this paper as [8]
Germ-free mice exhibit a persistently lean phenotype even when fed a high-fat diet.
“Germ-free mice exhibit a persistently lean phenotype even when fed a high-fat diet [49].”
From Gut Microbiota, Muscle Mass and Function in Aging: A Focus on Physical Frailty and Sarcopenia (2019) · cites this paper as [49]
The gut microbiota affects lipid metabolism and lipid levels in blood and tissues in mice and humans.
“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 [29]
Germ-free mice are protected against diet-induced obesity through a combination of several mechanisms including increased fatty acid oxidation and decreased deposition of triglycerides in adipocytes compared to conventionally raised mice.
“Importantly, GF mice are protected against diet-induced obesity through a combination of several mechanisms including increased fatty acid oxidation and decreased deposition of triglycerides in adipocytes compared to CONV-R mice [29].”
From Dietary lipids, gut microbiota and lipid metabolism (2019) · cites this paper as [29]
Particular population changes in the oral microbiota are associated with pathologies that confer an increased risk of developing PH and other vascular disease, including obesity, diabetes, and insulin resistance.
“there is evidence that particular population changes are associated with pathologies that confer an increased risk of developing PH and other vascular disease, including obesity[273–275], diabetes[276], and insulin resistance[277].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [273]
Germfree mice lacking a functional microbiome are resistant to diet-induced obesity on a western diet.
“germfree mice – which lack a functional microbiome – are resistant to diet-induced obesity on a western diet [7].”
From Gut microbiota and glucometabolic alterations in response to recurrent partial sleep deprivation in normal-weight young individuals (2016) · cites this paper as [7]
Compared to mice with gut microbiota, skeletal muscle from GF mice was characterized by markedly greater activity of AMPK and CPT-1, indicative of an elevated oxidative capacity.
“Compared to mice with gut microbiota, skeletal muscle from GF mice was characterized by markedly greater activity of AMP-activated protein kinase (AMPK) and carnitine palmitoyl transferase-1 (CPT-1), indicative of an elevated oxidative capacity.”
From Gut Microbiota Contribute to Age-Related Changes in Skeletal Muscle Size, Composition, and Function: Biological Basis for a Gut-Muscle Axis (2018) · cites this paper as [23]
Gut microbiota may impact distal metabolic activity in skeletal muscle tissues.
“evidence also suggests that gut microbiota may impact distal metabolic activity in skeletal muscle tissues [23, 30].”
From Gut Microbiota Contribute to Age-Related Changes in Skeletal Muscle Size, Composition, and Function: Biological Basis for a Gut-Muscle Axis (2018) · cites this paper as [23]
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- Authors
- Bäckhed, F., Manchester, J. K., Semenkovich, C. F., & Gordon, J. I.
- Affiliations
- Washington University in St. Louis (US)
- *Center for Genome Sciences and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-01-16
- Volume
- 104
- Issue
- 3
- Pages
- 979-984
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1764762
- OpenAlex
- W2042074642
- Cited by
- 2,615
- References
- 25
- Citations by year
- 2026: 59 · 2025: 87 · 2024: 100 · 2023: 140 · 2022: 176 · 2021: 204 · 2020: 202 · 2019: 197 · 2018: 193 · 2017: 173 · 2016: 183 · 2015: 165 · 2014: 135 · 2013: 131 · 2012: 129
- FWCI
- 30.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wenner-Gren Foundation
- National Institutes of Health (DK56341)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK 56431, DK 70977, R01DK070977, P30DK056341, P30DK056336)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- germ-free mice, gut microbiota, diet-induced obesity, AMPK, fatty acid oxidation, FIAF, PGC-1α, acetyl-CoA carboxylase, carnitine palmitoyltransferase, energy balance, skeletal muscle, liver, lipoprotein lipase inhibition
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Angiopoietin-Like Protein 4, Animals, Blood Proteins, Diet, Gene Expression Regulation, Germ-Free Life, Liver, Motor Activity, Multienzyme Complexes, Muscles, Obesity, Phosphorylation, Transcription Factors, Trans-Activators, Protein Serine-Threonine Kinases, Mice, Knockout, Angiopoietins, Mice, AMP-Activated Protein Kinases
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