ArticleThe Journal of clinical investigation2019
Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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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.
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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.
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Who cites it
62 citing papers in PubMed, 99 citations in OpenAlex.
- Lipid sensing and brain hormone receptors in food intake and glucose regulation.Nature reviews. Endocrinology · 2026Review
- The evolving therapeutic landscape of gut-pancreatic peptide signalling in metabolic disorders: from mono- to multi-agonist therapies.Bioscience reports · 2026Review
- GLP-1 and GIP: Magic bullet for musculoskeletal diseases?Journal of advanced research · 2026Review
- The role of GIP in carbohydrate metabolism: Implications in the development of therapies for T2DM, a narrative review.Histology and histopathology · 2026Review
- A metabolic comparison of GIPR agonism versus GIPR antagonism in male mice.Diabetes, obesity & metabolism · 2026Article
- Gut microbiota and spleen-strengthening and dampness-dispelling therapies in obesity and related metabolic disorders: key mechanisms and therapeutic potential.Frontiers in pharmacology · 2026Review
- Berberine combined with stachyose protects against obesity by modulating gut microbiota and increasing leptin sensitivity.Science China. Life sciences · 2026Article
- Revitalizing GIP: Therapeutic Potential in Metabolic and Neurodegenerative Disorders.Diabetes, metabolic syndrome and obesity : targets and therapy · 2026Review
- Tirzepatide Synergizes with Leptin on Weight Loss and Restoring Metabolic Homeostasis in Diet-induced Obesity Model.bioRxiv : the preprint server for biology · 2025Article
- Leptin and leptin resistance in obesity: current evidence, mechanisms and future directions.Endocrine connections · 2025Review
- Advancements and challenges in the management of obesity using pharmacotherapy (Review).Experimental and therapeutic medicine · 2025Review
- Physiology and clinical applications of GIP.Endocrine journal · 2025Review
- Gut commensal Phascolarctobacterium faecium retunes innate immunity to mitigate obesity and metabolic disease in mice.Nature microbiology · 2025Article
- GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice.Nature metabolism · 2025Article
- GIPR-Ab/GLP-1 peptide-antibody conjugate requires brain GIPR and GLP-1R for additive weight loss in obese mice.Nature metabolism · 2025Article
- Differences in GIP Receptor Expression by Feeding Status in the Mouse Brain.International journal of molecular sciences · 2025Article
- Lard intake results in better hypothalamic leptin responsiveness than beef tallow intake during overnutrition.PloS one · 2025Article
- The role of GIPR in food intake control.Frontiers in endocrinology · 2025Review
- Role of short-chain fatty acids in host physiology.Animal models and experimental medicine · 2024Review
- Adipose Tissue: A Novel Target of the Incretin Axis? A Paradigm Shift in Obesity-Linked Insulin Resistance.International journal of molecular sciences · 2024Review
2 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 8 institutions in 5 countries.
Funding
Abstract
Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.
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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.