ArticleThe Journal of biological chemistry2015
Lipid-induced Muscle Insulin Resistance Is Mediated by GGPPS via Modulation of the RhoA/Rho Kinase Signaling Pathway.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
24 citing papers in PubMed, 41 citations in OpenAlex.
- Advanced glycation end-products regulate extracellular matrix-adipocyte metabolic crosstalk in diabetes.Scientific reports · 2019Trial
- Skeletal muscle-specific deficiency of Rab geranylgeranyl transferase beta subunit induces myopathy and exacerbates the symptoms caused by HMG-CoA reductase deficiency in mice.Molecular metabolism · 2026Article
- ROCK signaling at the crossroads of redox stress, mitochondrial dynamics, and metabolic disease.Redox biology · 2026Review
- Hepatic GGPP triggers visceral adipose hypertrophy via binding with adipocyte ACSL1 in metabolic unhealthy obesity.Communications biology · 2026Article
- Impact of Lipids on Insulin Resistance: Insights from Human and Animal Studies.Drug design, development and therapy · 2024Review
- Fumigaclavine C ameliorates liver steatosis by attenuating hepatic de novo lipogenesis via modulation of the RhoA/ROCK signaling pathway.BMC complementary medicine and therapies · 2023Article
- Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target.Clinical and translational medicine · 2023Review
- Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis.Frontiers in endocrinology · 2022Review
- Targeting Small GTPases and Their Prenylation in Diabetes Mellitus.Journal of medicinal chemistry · 2021Review
- In vivo evaluation of combination therapy targeting the isoprenoid biosynthetic pathway.Pharmacological research · 2021Article
- GGPP depletion initiates metaflammation through disequilibrating CYB5R3-dependent eicosanoid metabolism.The Journal of biological chemistry · 2020Article
- GGPS1 Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome.Annals of neurology · 2020Article
- The balance of protein farnesylation and geranylgeranylation during the progression of nonalcoholic fatty liver disease.The Journal of biological chemistry · 2020Review
- Liver governs adipose remodelling via extracellular vesicles in response to lipid overload.Nature communications · 2020Article
- Tissue-Specific Approaches Reveal Diverse Metabolic Functions of Rho-Kinase 1.Frontiers in endocrinology · 2020Review
- Metformin Ameliorates Lipotoxic β-Cell Dysfunction through a Concentration-Dependent Dual Mechanism of Action.Diabetes & metabolism journal · 2019Article
- Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome.Nature medicine · 2019Article
- Metabolic regulation through the endosomal system.Traffic (Copenhagen, Denmark) · 2019Review
- Review
- HSC-specific knockdown of GGPPS alleviated CClAmerican journal of translational research · 2019Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Elevated circulating free fatty acid levels are important contributors to insulin resistance in the muscle and liver, but the underlying mechanisms require further elucidation. Here, we show that geranylgeranyl diphosphate synthase 1 (GGPPS), which is a branch point enzyme in the mevalonic acid pathway, promotes lipid-induced muscle insulin resistance through activation of the RhoA/Rho kinase signaling pathway. We have found that metabolic perturbation would increase GGPPS expression in the skeletal muscles of db/db mice and high fat diet-fed mice. To address the metabolic effects of GGPPS activity in skeletal muscle, we generated mice with specific GGPPS deletions in their skeletal muscle tissue. Heterozygous knock-out of GGPPS in the skeletal muscle improved systemic insulin sensitivity and glucose homeostasis in mice fed both normal chow and high fat diets. These metabolic alterations were accompanied by activated PI3K/Akt signaling and enhanced glucose uptake in the skeletal muscle. Further investigation showed that the free fatty acid-stimulated GGPPS expression in the skeletal muscle was able to enhance the geranylgeranylation of RhoA, which further induced the inhibitory phosphorylation of IRS-1 (Ser-307) by increasing Rho kinase activity. These results implicate a crucial role of the GGPPS/RhoA/Rho kinase/IRS-1 pathway in skeletal muscle, in which it mediates lipid-induced systemic insulin resistance in obese mice. Therefore, skeletal muscle GGPPS may represent a potential pharmacological target for the prevention and treatment of obesity-related type 2 diabetes.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.