Gut hormone GIP induces inflammation and insulin resistance in the hypothalamus

Fu, Yukiko; Kaneko, Kentaro; Lin, Hsiao-Yun; Mo, Qianxing; Xu, Yong; Suganami, Takayoshi; Ravn, Peter; Fukuda, Makoto

doi:10.1210/endocr/bqaa102

Cited by 38Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesHypothalamic control of reproductive hormones

Gut hormone GIP induces inflammation and insulin resistance in the hypothalamus

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Fu, Yukiko, Kaneko, Kentaro, Lin, Hsiao-Yun, Mo, Qianxing, Xu, Yong, Suganami, Takayoshi, Ravn, Peter, Fukuda, Makoto·2020·Endocrinology

DOI 10.1210/endocr/bqaa102PMC PMC7410368

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Abstract

The hypothalamus plays a critical role in controlling energy balance. High-fat diet (HFD) feeding increases the gene expression of proinflammatory mediators and decreases insulin actions in the hypothalamus. Here, we show that a gut-derived hormone, glucose-dependent insulinotropic polypeptide (GIP), whose levels are elevated during diet-induced obesity, promotes and mediates hypothalamic inflammation and insulin resistance during HFD-induced obesity. Unbiased ribonucleic acid sequencing of GIP-stimulated hypothalami revealed that hypothalamic pathways most affected by intracerebroventricular (ICV) GIP stimulation were related to inflammatory-related responses. Subsequent analysis demonstrated that GIP administered either peripherally or centrally, increased proinflammatory-related factors such as Il-6 and Socs3 in the hypothalamus, but not in the cortex of C57BL/6J male mice. Consistently, hypothalamic activation of IκB kinase-β inflammatory signaling was induced by ICV GIP. Further, hypothalamic levels of proinflammatory cytokines and Socs3 were significantly reduced by an antagonistic GIP receptor (GIPR) antibody and by GIPR deficiency. Additionally, centrally administered GIP reduced anorectic actions of insulin in the brain and diminished insulin-induced phosphorylation of Protein kinase B and Glycogen synthase kinase 3β in the hypothalamus. Collectively, these findings reveal a previously unrecognized role for brain GIP signaling in diet-induced inflammation and insulin resistance in the hypothalamus.

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GIP administration promotes preadipocyte differentiation and fat storage, and, in the brain, inflammation and insulin resistance.
“GIP administration promotes preadipocyte differentiation and fat storage, and, in the brain, inflammation and insulin resistance.”
From The carbohydrate-insulin model: A physiological perspective on the obesity pandemic (2021) · cites this paper as [77]
GIP receptor knockout mice are protected against diet-induced obesity.
“GIP receptor knockout mice are protected against diet-induced obesity (36, 75–78).”
From The carbohydrate-insulin model: A physiological perspective on the obesity pandemic (2021) · cites this paper as [77]

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Authors: Fu, Y., Kaneko, K., Lin, H.-Y., Mo, Q., Xu, Y., Suganami, T., Ravn, P., & Fukuda, M.
Affiliations: Baylor College of Medicine (US)
Research Institute of Environmental Medicine, Nagoya University (JP)
AstraZeneca (United Kingdom) (GB)
Corresponding author: Mo, Qianxing
Fukuda, Makoto
ORCID: Fu, Yukiko
Kaneko, Kentaro
Lin, Hsiao-Yun
Mo, Qianxing
Xu, Yong
Suganami, Takayoshi
Ravn, Peter
Fukuda, Makoto
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2020-06-30
Volume: 161
Issue: 9
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/endocr/bqaa102
PMC: PMC7410368
OpenAlex: W3038304001
Cited by: 38
References: 86
Citations by year: 2026: 2 · 2025: 10 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 7 · 2020: 2
FWCI: 2.69
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations: Endocrinology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Department of Agriculture
Agriculture Research Services (AHA-14BGIA20460080, 6250-51000-055, NIH-P30-DK079638)
National Institutes of Health (R01DK104901, AHA-15POST22500012)
Uehara Memorial Foundation (201340214)
P30 Digestive Disease Center Support (NIDDK-DK56338)
P30 Cancer Center Support (NCI-CA125123)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords: glucose-dependent insulinotropic polypeptide, hypothalamus, hypothalamic inflammation, insulin resistance, diet-induced obesity, high-fat diet, gut-brain axis, GIP receptor, interleukin-6, SOCS3, insulin signaling, Akt, glycogen synthase kinase-3β, energy balance
MeSH terms: Animals, Encephalitis, Gastric Inhibitory Polypeptide, Hypothalamus, Inflammation, Insulin Resistance, Male, Mice, Inbred C57BL, Mice, Obese, Receptors, Gastrointestinal Hormone, Signal Transduction, Up-Regulation, Mice, Knockout, Mice, Infusions, Intraventricular, Diet, High-Fat

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Gut hormone GIP induces inflammation and insulin resistance in the hypothalamus

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