CoChat
Sign Up
Cited by 875Regulation of Appetite and ObesityEndoplasmic Reticulum Stress and DiseaseAdipokines, Inflammation, and Metabolic Diseases

Endoplasmic Reticulum Stress Plays a Central Role in Development of Leptin Resistance

Open access
Ozcan, Lale, Ergin, Ayse Seda, Lu, Allen, Chung, Jason, Sarkar, Sumit, Nie, Duyu, Myers, Martin G., Ozcan, Umut·2009·Cell Metabolism
DOI 10.1016/j.cmet.2008.12.004
Open this paper in CoChat — free accountOpen PDF

Abstract

Leptin has not evolved as a therapeutic modality for the treatment of obesity due to the prevalence of leptin resistance in a majority of the obese population. Nevertheless, the molecular mechanisms of leptin resistance remain poorly understood. Here, we show that increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in the hypothalamus of obese mice inhibits leptin receptor signaling. The genetic imposition of reduced ER capacity in mice results in severe leptin resistance and leads to a significant augmentation of obesity on a high-fat diet. Moreover, we show that chemical chaperones, 4-phenyl butyric acid (PBA), and tauroursodeoxycholic acid (TUDCA), which have the ability to decrease ER stress, act as leptin-sensitizing agents. Taken together, our results may provide the basis for a novel treatment of obesity.

Integrity signals

Registry

Crossref · 10.1016/j.cmet.2008.12.004

Cites

39 of 39 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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 [121]

  • Neuronal deletion of X-box binding protein-1 in mice increased food intake and body adiposity and is accompanied by hypothalamic leptin resistance.

    “neuronal deletion of X-box binding protein-1 (XBP-1) in mice increased food intake and body adiposity, and is accompanied by hypothalamic leptin resistance (140).”

    From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [140]

  • Induction of ER stress in the brain of mice and rats increases food intake and body weight and blocks the anorexic effects of insulin and leptin.

    “induction of ER stress in the brain of mice and rats increases food intake and body weight and blocks the anorexic effects of insulin and leptin (140, 199).”

    From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [140]

  • ER stress and the unfolded protein response are activated in the hypothalamus of obese mice, and this effect is sufficient to inhibit leptin signaling.

    “Recent studies demonstrate that ER stress and the unfolded protein response (UPR) are activated in the hypothalamus of obese mice and that this effect is sufficient to inhibit leptin signaling (140).”

    From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [140]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Ozcan, L., Ergin, A. S., Lu, A., Chung, J., Sarkar, S., Nie, D., Myers, M. G., & Ozcan, U.
Affiliations
  • Boston Children's Hospital (US)
  • University of Michigan (US)
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2009-01
Volume
9
Issue
1
Pages
35-51
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2008.12.004
OpenAlex
W2169612876
Cited by
875
References
39
Citations by year
2026: 24 · 2025: 20 · 2024: 17 · 2023: 35 · 2022: 27 · 2021: 48 · 2020: 29 · 2019: 55 · 2018: 58 · 2017: 55 · 2016: 69 · 2015: 59 · 2014: 71 · 2013: 70 · 2012: 72
FWCI
35.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Funders
U.S. Food and Drug Administration
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
leptin resistance, endoplasmic reticulum stress, unfolded protein response, hypothalamus, leptin receptor signaling, obesity, high-fat diet, chemical chaperones, 4-phenylbutyric acid, tauroursodeoxycholic acid
MeSH terms
Animals, Endoplasmic Reticulum, Hypothalamus, Mice, Inbred C57BL, Mice, Obese, Obesity, Phenylbutyrates, Taurochenodeoxycholic Acid, Tunicamycin, Signal Transduction, Leptin, Mice, Receptors, Leptin

About these checks

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review