Consumption of a Fat-Rich Diet Activates a Proinflammatory Response and Induces Insulin Resistance in the Hypothalamus
Abstract
Obesity has reached epidemic proportions in several regions of the world. General changes in lifestyle, including consumption of fat-rich food, are among the most important factors leading to an unprecedented increase in the prevalence of this disease. Weight gain results from an imbalance between caloric intake and energy expenditure. Both of these parameters are under the tight control of specialized neurons of the hypothalamus that respond to peripheral anorexigenic and adipostatic signals carried by leptin and insulin. Here we show, by macroarray analysis, that high-fat feeding [hyperlipidic diet (HL)] induces the expression of several proinflammatory cytokines and inflammatory responsive proteins in hypothalamus. This phenomenon is accompanied by increased activation of c-Jun N-terminal kinase and nuclear factor-kappaB. In addition, HL feeding leads to impaired functional and molecular activation of the insulin-signaling pathway, which is paralleled by increased serine phosphorylation of the insulin receptor and insulin receptor substrate-2. Intracerebroventricular treatment of HL rats with a specific inhibitor of c-Jun N-terminal kinase (SP600125) restores insulin signaling and leads to a reduced caloric intake and weight loss. We conclude that HL feeding induces a local proinflammatory status in the hypothalamus, which results in impaired anorexigenic insulin signaling.
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The obesity-induced toxic internal environment does not spare the brain.
“It is becoming clear that the obesity-induced toxic internal environment does not spare the brain ([24](#B24), [46](#B46), [48](#B48), [52](#B52), [59](#B59), [95](#B95), [121](#B121), [127](#B127), [177](#B177), [182](#B182), [198](#B198)).”
From Food reward, hyperphagia, and obesity (2011) · cites this paper as [48]
High-fat diets disturb the relationship between glial cells and neurons in the hypothalamus through increased endoplasmic reticulum and oxidative stress, leading to stress-response pathways with generally cytotoxic effects.
“A number of recent studies directed attention to the hypothalamus, where high-fat diets disturb the delicate relationship between glial cells and neurons through increased endoplasmic reticulum and oxidative stress, leading to stress-response pathways with generally cytotoxic effects ([48](#B48), [121](#B121), [177](#B177), [198](#B198)).”
From Food reward, hyperphagia, and obesity (2011) · cites this paper as [48]
Obesity may induce brain insulin resistance through mechanisms including adipose tissue inability to store fatty acids leading to their accumulation in brain, pro-inflammatory macrophages producing cytokines that cross the blood-brain barrier and induce central inflammation, and nutrient overload causing mitochondrial dysfunction and oxidative stress.
“Obesity may induce brain insulin resistance through several mechanisms: 1) in obesity conditions the adipose tissue loses its ability to store fatty acids, thereby inducing their accumulation in other tissues including the brain, which consequently develop insulin resistance (Engin, 2017); 2) in the adipose tissue of obese people, macrophages become pro-inflammatory and produce inflammatory”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as De Souza et al., 2005
AGEs can activate pro-inflammatory pathways; JNK and IKK/NF-κB have been implicated in mediating high-fat diet-induced hypothalamic insulin and leptin resistance leading to hypothalamic dysfunction.
“AGEs can also activate pro-inflammatory pathways; JNK and IKK/NF-𝜅B both of which have been implicated in mediating high-fat diet induced hypothalamic insulin and leptin resistance leading to hypothalamic dysfunction.[145][146][147][148][149]”
From The Role of Dietary Advanced Glycation End Products in Metabolic Dysfunction (2021) · cites this paper as [147]
Rats fed a high-fat diet for 20 weeks exhibit both leptin resistance and hypothalamic inflammation, as measured by elevated mRNA and protein levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 resulting from activation of IKKβ and JNK-1.
“rats fed a HFD for 20-weeks exhibit both leptin resistance and hypothalamic inflammation, as measured by elevated mRNA and protein levels of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) resulting from activation of IKKβ and JNK-1 (45, 148, 211).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [45]
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Legend of Weight Loss: A Crosstalk Between the Bariatric Surgery and the Brain
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- Authors
- De Souza, C. T., Araujo, E. P., Bordin, S., Ashimine, R., Zollner, R. L., Boschero, A. C., Saad, M. J. A., & Velloso, L. A.
- Affiliations
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Universidade de São Paulo (BR)
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2005-10
- Volume
- 146
- Issue
- 10
- Pages
- 4192-4199
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W1964562779
- Cited by
- 1,171
- References
- 30
- Citations by year
- 2026: 26 · 2025: 43 · 2024: 57 · 2023: 56 · 2022: 70 · 2021: 70 · 2020: 79 · 2019: 77 · 2018: 74 · 2017: 85 · 2016: 78 · 2015: 73 · 2014: 84 · 2013: 68 · 2012: 67
- FWCI
- 6.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion)
- Americanae (AECID Library) (submittedVersion)
- Funders
- Universidade Estadual de Campinas
- 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
- high-fat diet, hypothalamus, insulin resistance, inflammatory cytokines, obesity, c-Jun N-terminal kinase, NF-κB, insulin signaling, insulin receptor substrate 2, leptin, appetite regulation, energy intake, SP600125, weight loss
- MeSH terms
- Adipose Tissue, Animals, Appetite, Base Sequence, Energy Intake, Dietary Fats, Epididymis, Hypothalamus, Inflammation, Injections, Intraventricular, Insulin, Insulin Resistance, Male, NF-kappa B, Rats, Wistar, DNA Primers, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Rats
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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