Cited by 488Endoplasmic Reticulum Stress and DiseaseAdipokines, Inflammation, and Metabolic DiseasesBariatric Surgery and Outcomes

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Endoplasmic Reticulum Stress Is Reduced in Tissues of Obese Subjects After Weight Loss

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Gregor, Margaret F., Yang, Ling, Fabbrini, Elisa, Mohammed, B. Selma, Eagon, J. Christopher, Hotamisligil, Gökhan S., Klein, Samuel·2009·Diabetes

DOI 10.2337/db08-1220PMC PMC2646068

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Abstract

OBJECTIVE: Obesity is associated with insulin resistance and type 2 diabetes, although the mechanisms linking these pathologies remain undetermined. Recent studies in rodent models revealed endoplasmic reticulum (ER) stress in adipose and liver tissues and demonstrated that ER stress could cause insulin resistance. Therefore, we tested whether these stress pathways were also present in obese human subjects and/or regulated by weight loss. RESEARCH DESIGN AND METHODS: Eleven obese men and women (BMI 51.3 +/- 3.0 kg/m2) were studied before and 1 year after gastric bypass (GBP) surgery. We examined systemic insulin sensitivity using hyperinsulinemic-euglycemic clamp studies before and after surgery and collected subcutaneous adipose and liver tissues to examine ER stress markers. RESULTS: Subjects lost 39 +/- 9% body wt at 1 year after GBP surgery (P < 0.001), which was associated with a marked improvement in hepatic, skeletal muscle, and adipose tissue insulin sensitivity. Markers of ER stress in adipose tissue significantly decreased with weight loss. Specifically, glucose-regulated protein 78 (Grp78) and spliced X-box binding protein-1 (sXBP-1) mRNA levels were reduced, as were phosphorylated elongation initiation factor 2alpha (eIF2alpha) and stress kinase c-Jun NH2-terminal kinase 1 (JNK1) (all P values <0.05). Liver sections from a subset of subjects showed intense staining for Grp78 and phosphorylated eIF2alpha before surgery, which was reduced in post-GBP sections. CONCLUSIONS: This study presents important evidence that ER stress pathways are present in selected tissues of obese humans and that these signals are regulated by marked weight loss and metabolic improvement. Hence, this suggests the possibility of a relationship between obesity-related ER stress and metabolic dysfunction in obese humans.

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“In addition to the inflammatory effects, the activation of endoplasmic reticulum (ER) stress-mediated signaling pathways by FFAs has been linked to obesity-associated immunometabolic dysregulation and insulin resistance (17, 18).”
Background
Laparoscopic sleeve gastrectomy reverses non-alcoholic fatty liver disease modulating oxidative stress and inflammation
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BackgroundInfluential
Polysome Profiling in Liver Identifies Dynamic Regulation of Endoplasmic Reticulum Translatome by Obesity and Fasting
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Maternal obesity: new placental paradigms unfolded
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The Effect of Chronic Inflammation and Oxidative and Endoplasmic Reticulum Stress in the Course of Metabolic Syndrome and Its Therapy
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Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus
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Background

Authors: Gregor, M. F., Yang, L., Fabbrini, E., Mohammed, B. S., Eagon, J. C., Hotamisligil, G. S., & Klein, S.
Affiliations: Harvard University (US)
Washington University in St. Louis (US)
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts
Corresponding author: Klein, Samuel
ORCID: Gregor, Margaret F.
Yang, Ling
Fabbrini, Elisa
Eagon, J. Christopher
Klein, Samuel
Venue: Diabetes
Publisher: American Diabetes Association
Published: 2009-03-01
Volume: 58
Issue: 3
Pages: 693-700
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/db08-1220
PMC: PMC2646068
OpenAlex: W2122631753
Cited by: 488
References: 29
Citations by year: 2026: 7 · 2025: 13 · 2024: 16 · 2023: 22 · 2022: 22 · 2021: 22 · 2020: 25 · 2019: 19 · 2018: 28 · 2017: 31 · 2016: 32 · 2015: 47 · 2014: 38 · 2013: 42 · 2012: 43
FWCI: 11.82
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
Locations: Diabetes (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
Funders: American Diabetes Association
National Institutes of Health (5t32es007155-24, UL1TR000448)
National Institute of Diabetes and Digestive and Kidney Diseases (DK52539, DK37948, DK56341, R01DK037948, R01DK052539, P30DK056341, P30DK040561)
National Institute of Environmental Health Sciences (T32-ES007155, T32 ES007155-24)
National Center for Research Resources (UL1RR024992)
National Center for Advancing Translational Sciences
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
Keywords: endoplasmic reticulum stress, obesity, weight loss, gastric bypass, insulin resistance, type 2 diabetes, adipose tissue, liver, skeletal muscle, GRP78, eIF2α, JNK1, insulin sensitivity
MeSH terms: Endoplasmic Reticulum Chaperone BiP, Adipose Tissue, Endoplasmic Reticulum, Female, Follow-Up Studies, Humans, Hyperinsulinism, Insulin Resistance, Liver, Male, Middle Aged, Obesity, Stress, Physiological, Glucose Clamp Technique, Gastric Bypass, Muscle, Skeletal

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Endoplasmic Reticulum Stress Is Reduced in Tissues of Obese Subjects After Weight Loss

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