Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance
Open accessAbstract
Insulin resistance in skeletal muscle and liver may play a primary role in the development of type 2 diabetes mellitus, and the mechanism by which insulin resistance occurs may be related to alterations in fat metabolism. Transgenic mice with muscle- and liver-specific overexpression of lipoprotein lipase were studied during a 2-h hyperinsulinemic–euglycemic clamp to determine the effect of tissue-specific increase in fat on insulin action and signaling. Muscle–lipoprotein lipase mice had a 3-fold increase in muscle triglyceride content and were insulin resistant because of decreases in insulin-stimulated glucose uptake in skeletal muscle and insulin activation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity. In contrast, liver–lipoprotein lipase mice had a 2-fold increase in liver triglyceride content and were insulin resistant because of impaired ability of insulin to suppress endogenous glucose production associated with defects in insulin activation of insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity. These defects in insulin action and signaling were associated with increases in intracellular fatty acid-derived metabolites (i.e., diacylglycerol, fatty acyl CoA, ceramides). Our findings suggest a direct and causative relationship between the accumulation of intracellular fatty acid-derived metabolites and insulin resistance mediated via alterations in the insulin signaling pathway, independent of circulating adipocyte-derived hormones.
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Previous studies by our group and others have demonstrated a strong relationship between triglyceride content in liver and muscle and insulin resistance in these tissues.
“Previous studies by our group (9, 17-20) and others (7, 21, 22) have demonstrated a strong relationship between triglyceride content in liver and muscle and insulin resistance in these tissues.”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [20]
Muscle-specific overexpression of lipoprotein lipase leads to accumulation of fat and fatty acyl-CoA in muscle and severe muscle insulin resistance, while fat content and insulin sensitivity in other tissues such as liver remain unchanged.
“(vi) muscle-specific over expression of lipoprotein lipase leads to the accumulation of fat/FACoA in muscle and severe muscle insulin resistance, while the fat content and insulin sensitivity in other tissues, that is, liver, remain unchanged [78];”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [78]
Genetic murine models have established that tissue-specific overexpression of lipoprotein lipase promotes tissue-specific lipid accumulation and selective insulin resistance.
“Genetic murine models have been invaluable in establishing this theory—eg, tissue-specific overexpression of lipoprotein lipase promotes tissue-specific lipid accumulation and selective insulin resistance.47”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [47]
NAFLD-induced hepatic insulin resistance is a major factor responsible for the transition from normoglycemia to fasting hyperglycemia and T2DM.
“recent studies have demonstrated that NAFLD-induced hepatic insulin resistance is a major factor responsible for the transition from normoglycemia to fasting hyperglycemia and T2DM (18–23).”
From The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome (2007) · cites this paper as [19]
NAFLD is strongly linked to hepatic insulin resistance.
“NAFLD is strongly linked to hepatic insulin resistance”
From The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome (2007) · cites this paper as [19]
There is increasing evidence for a causal relationship between hepatic steatosis and hepatic insulin resistance in rodent models and in patients with nonalcoholic fatty liver disease.
“There is increasing evidence for a causal relationship between hepatic steatosis and hepatic insulin resistance both in rodent models with hepatic steatosis and in patients with nonalcoholic fatty liver disease (4, 18-25).”
From Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men (2006) · cites this paper as [23]
Transgenic mice expressing lipoprotein lipase in the liver have a 2-fold increase in hepatic triglyceride content and are insulin resistant.
“Transgenic mice expressing lipoprotein lipase in the liver have a 2-fold increase in hepatic triglyceride content and are insulin resistant (219).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [219]
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- Authors
- Kim, J. K., Fillmore, J. J., Chen, Y., Yu, C., Moore, I. K., Pypaert, M., Lutz, E. P., Kako, Y., Velez-Carrasco, W., Goldberg, I. J., Breslow, J. L., & Shulman, G. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- Howard Hughes Medical Institute and Departments of Internal Medicine, Cellular and Molecular Physiology, and Cell Biology, Yale University School of Medicine, New Haven, CT 06510; Department of Medicine, Columbia University, New York, NY 10032; and Laboratory of Biochemical Genetics and Metabolism, Rockefeller University, New York, NY 10021
- Corresponding author
- Shulman, Gerald I.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-06-05
- Volume
- 98
- Issue
- 13
- Pages
- 7522-7527
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC34701
- OpenAlex
- W2137842897
- Cited by
- 753
- References
- 37
- Citations by year
- 2026: 1 · 2025: 12 · 2024: 26 · 2023: 23 · 2022: 25 · 2021: 15 · 2020: 23 · 2019: 17 · 2018: 22 · 2017: 25 · 2016: 28 · 2015: 28 · 2014: 21 · 2013: 28 · 2012: 25
- FWCI
- 34.12
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080756, R01DK040936)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- lipoprotein lipase, insulin resistance, type 2 diabetes, skeletal muscle, liver, liver triglyceride accumulation, insulin-stimulated glucose uptake, IRS-1, insulin receptor substrate 2, phosphatidylinositol 3-kinase, insulin signaling, endogenous glucose production, diacylglycerol, ceramide, fatty acyl-CoA, transgenic mice
- MeSH terms
- Animals, Blood Glucose, Fatty Acids, Nonesterified, Glucagon, Glucose, Glucose Tolerance Test, Heterozygote, Insulin, Insulin Resistance, Lipoprotein Lipase, Liver, Mice, Transgenic, Organ Specificity, Phosphoproteins, Triglycerides, Glucose Clamp Technique, Signal Transduction, Mice, Knockout, Muscle, Skeletal, Phosphatidylinositol 3-Kinases, Leptin, Mice, Insulin Receptor Substrate Proteins
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