Time-Resolved and Tissue-Specific Systems Analysis of the Pathogenesis of Insulin Resistance
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BACKGROUND: The sequence of events leading to the development of insulin resistance (IR) as well as the underlying pathophysiological mechanisms are incompletely understood. As reductionist approaches have been largely unsuccessful in providing an understanding of the pathogenesis of IR, there is a need for an integrative, time-resolved approach to elucidate the development of the disease. METHODOLOGY/PRINCIPAL FINDINGS: Male ApoE3Leiden transgenic mice exhibiting a humanized lipid metabolism were fed a high-fat diet (HFD) for 0, 1, 6, 9, or 12 weeks. Development of IR was monitored in individual mice over time by performing glucose tolerance tests and measuring specific biomarkers in plasma, and hyperinsulinemic-euglycemic clamp analysis to assess IR in a tissue-specific manner. To elucidate the dynamics and tissue-specificity of metabolic and inflammatory processes key to IR development, a time-resolved systems analysis of gene expression and metabolite levels in liver, white adipose tissue (WAT), and muscle was performed. During HFD feeding, the mice became increasingly obese and showed a gradual increase in glucose intolerance. IR became first manifest in liver (week 6) and then in WAT (week 12), while skeletal muscle remained insulin-sensitive. Microarray analysis showed rapid upregulation of carbohydrate (only liver) and lipid metabolism genes (liver, WAT). Metabolomics revealed significant changes in the ratio of saturated to polyunsaturated fatty acids (liver, WAT, plasma) and in the concentrations of glucose, gluconeogenesis and Krebs cycle metabolites, and branched amino acids (liver). HFD evoked an early hepatic inflammatory response which then gradually declined to near baseline. By contrast, inflammation in WAT increased over time, reaching highest values in week 12. In skeletal muscle, carbohydrate metabolism, lipid metabolism, and inflammation was gradually suppressed with HFD. CONCLUSIONS/SIGNIFICANCE: HFD-induced IR is a time- and tissue-dependent process that starts in liver and proceeds in WAT. IR development is paralleled by tissue-specific gene expression changes, metabolic adjustments, changes in lipid composition, and inflammatory responses in liver and WAT involving p65-NFkB and SOCS3. The alterations in skeletal muscle are largely opposite to those in liver and WAT.
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Mouse visceral adipose tissue weight can double within one week of starting a high-fat diet.
“The mouse visceral AT weight can double within one week of the initiation of a high-fat diet (HFD) (2) but can undergo a dramatic reduction within 24 hours of fasting.”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [2]
ApoE3-Leiden mice display increased acute-phase response genes within one week of high-fat feeding and increased chronic inflammatory responses after six weeks.
“For instance, ApoE3-Leiden mice, which exhibit a more humanized lipid metabolism compared with WT mice, display increased acute-phase response genes within one week of HFF, whereas chronic inflammatory responses are increased after six weeks of HFF (2).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [2]
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The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis.
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- Authors
- Kleemann, R., van Erk, M., Verschuren, L., van den Hoek, A. M., Koek, M., Wielinga, P. Y., Jie, A., Pellis, L., Bobeldijk-Pastorova, I., Kelder, T., Toet, K., Wopereis, S., Cnubben, N., Evelo, C., van Ommen, B., & Kooistra, T.
- Affiliations
- Netherlands Organisation for Applied Scientific Research (NL)
- Maastricht University (NL)
- Corresponding author
- Kleemann, Robert
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-01-21
- Volume
- 5
- Issue
- 1
- Pages
- e8817
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2809107
- OpenAlex
- W2034086375
- Cited by
- 146
- References
- 61
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 6 · 2018: 4 · 2017: 16 · 2016: 8 · 2015: 7 · 2014: 15 · 2013: 19 · 2012: 26
- FWCI
- 15.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- TNO Repository (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
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- Repository hosted by TU Delft Library (TU Delft) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- insulin resistance, high-fat diet, hepatic insulin resistance, white adipose tissue, skeletal muscle insulin sensitivity, tissue-specific gene expression, fatty acid composition, liver inflammation, NF-κB p65, SOCS3, gluconeogenesis, branched-chain amino acids, glucose tolerance, obesity
- MeSH terms
- Animals, Fatty Acids, Nonesterified, Glucose Tolerance Test, Insulin Resistance, Male, Mice, Transgenic, Blotting, Western, Oligonucleotide Array Sequence Analysis, Adiposity, Mice, Apolipoprotein E3
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