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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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FIG. 1. Alterations in systemic insulin sensitivity in GBP subjects. Hepatic insulin sensitivity index, calculated as the reciprocal of the product of basal glucose production and insulin concentration (A); insulin-stimulated glucose disposal, an index of skeletal muscle insulin sensitivity assessed as the relative increase in glucose uptake during insulin infusion (B); and insulin-mediated suppression of palmitate Ra into plasma, an index of adipose tissue insulin sensitivity assessed as the relative decrease in palmitate Ra during insulin infusion (C), in obese subjects before (▪) and 1 year after (□) GBP surgery. *Value significantly different from the before GBP value; *P < 0.01, **P < 0.001.
FIG. 1. Alterations in systemic insulin sensitivity in GBP subjects. Hepatic insulin sensitivity index, calculated as the reciprocal of the product of basal glucose production and insulin concentration (A); insulin-stimulated glucose disposal, an index of skeletal muscle insulin sensitivity assessed as the relative increase in glucose uptake during insulin infusion (B); and insulin-mediated suppression of palmitate Ra into plasma, an index of adipose tissue insulin sensitivity assessed as the relative decrease in palmitate Ra during insulin infusion (C), in obese subjects before (▪) and 1 year after (□) GBP surgery. *Value significantly different from the before GBP value; *P < 0.01, **P < 0.001.CC BY-NC-ND · PubMed Central
FIG. 2. Regulation of spliced XBP-1 mRNA in GBP subjects. Quantitative RT-PCR was performed on RNA isolated from adipose tissue of patients before and after GBP surgery, n = 11. A: Percent change in sXBP-1 mRNA from pre-GBP levels in each individual patient. B: Pre- and post-GBP surgery levels of sXBP-1 mRNA normalized to 18S ribosomal RNA. C: Average mRNA levels for sXBP-1 in pre and post-GBP surgery groups. Data indicate means ± SE. *P < 0.05.
FIG. 2. Regulation of spliced XBP-1 mRNA in GBP subjects. Quantitative RT-PCR was performed on RNA isolated from adipose tissue of patients before and after GBP surgery, n = 11. A: Percent change in sXBP-1 mRNA from pre-GBP levels in each individual patient. B: Pre- and post-GBP surgery levels of sXBP-1 mRNA normalized to 18S ribosomal RNA. C: Average mRNA levels for sXBP-1 in pre and post-GBP surgery groups. Data indicate means ± SE. *P < 0.05.CC BY-NC-ND · PubMed Central
FIG. 3. Regulation of Grp78 mRNA in GBP subjects. Quantitative RT-PCR was performed on RNA isolated from adipose tissue of patients before and after GBP, n = 11. A: Percent change in Grp78 mRNA from pre-GBP levels in each individual patient. B: Pre- and post-GBP surgery levels of Grp78 mRNA normalized to 18S ribosomal RNA. C: Average mRNA levels for Grp78 in pre- and post-GBP groups. Data indicate mean ± SE. *P < 0.02.
FIG. 3. Regulation of Grp78 mRNA in GBP subjects. Quantitative RT-PCR was performed on RNA isolated from adipose tissue of patients before and after GBP, n = 11. A: Percent change in Grp78 mRNA from pre-GBP levels in each individual patient. B: Pre- and post-GBP surgery levels of Grp78 mRNA normalized to 18S ribosomal RNA. C: Average mRNA levels for Grp78 in pre- and post-GBP groups. Data indicate mean ± SE. *P < 0.02.CC BY-NC-ND · PubMed Central
FIG. 4. CHOP (left panel) and IL-6 (right panel) mRNA levels in GBP subjects. Quantitative RT-PCR was performed on RNA isolated from adipose tissue of patients before and after GBP, n = 11. A: Percent change in CHOP and IL-6 mRNA from pre-GBP levels in each individual patient. B: Pre- and post-GBP levels of CHOP and IL-6 mRNA normalized to 18S ribosomal RNA. C: Average mRNA levels for CHOP and IL-6 in pre- and post-GBP groups. Data indicate means ± SE. *P < 0.05.
FIG. 4. CHOP (left panel) and IL-6 (right panel) mRNA levels in GBP subjects. Quantitative RT-PCR was performed on RNA isolated from adipose tissue of patients before and after GBP, n = 11. A: Percent change in CHOP and IL-6 mRNA from pre-GBP levels in each individual patient. B: Pre- and post-GBP levels of CHOP and IL-6 mRNA normalized to 18S ribosomal RNA. C: Average mRNA levels for CHOP and IL-6 in pre- and post-GBP groups. Data indicate means ± SE. *P < 0.05.CC BY-NC-ND · PubMed Central
FIG. 5. Adipose tissue p-eIF2α and p-JNK levels after GBP surgery. Protein expression levels of p-eIF2α and p-JNK in adipose tissue from patients before and after GBP were detected by Western blot assay, followed by densitometric analysis. A: Pre- and post-GBP levels of p-eIF2α and p-JNK normalized to calnexin. B: Average levels of p-eIF2α and p-JNK in pre- and post-GBP groups. C: Immunoblot analyses of p-eIF2α and p-JNK expression levels in patients 67, 68, and 71 before and after GBP. Data indicate means ± SE. *P < 0.05. (Please see http://dx.doi.org/10.2337/db08-1220 for a high-quality digital representation of this figure.)
FIG. 5. Adipose tissue p-eIF2α and p-JNK levels after GBP surgery. Protein expression levels of p-eIF2α and p-JNK in adipose tissue from patients before and after GBP were detected by Western blot assay, followed by densitometric analysis. A: Pre- and post-GBP levels of p-eIF2α and p-JNK normalized to calnexin. B: Average levels of p-eIF2α and p-JNK in pre- and post-GBP groups. C: Immunoblot analyses of p-eIF2α and p-JNK expression levels in patients 67, 68, and 71 before and after GBP. Data indicate means ± SE. *P < 0.05. (Please see http://dx.doi.org/10.2337/db08-1220 for a high-quality digital representation of this figure.)CC BY-NC-ND · PubMed Central
FIG. 6. Liver histology and p-eIF2α and Grp78 immunoreactivity after GBP. Liver tissue sections from patient 67 obtained during and after GBP surgery were stained with H-E or with antibodies against p-eIF2α (green) or Grp78 (red). Nuclei are stained with DAPI (blue). The top panel illustrates severe steatosis in the pre-GBP sample and marked reduction after GBP. Staining is particularly dense around the lipid droplets (black in the stained samples). Quantification of staining is presented as relative intensity of fluorescence in pre- and post-GBP sections. *P < 0.01. (Please see http://dx.doi.org/10.2337/db08-1220 for a high-quality digital representation of this figure.)
FIG. 6. Liver histology and p-eIF2α and Grp78 immunoreactivity after GBP. Liver tissue sections from patient 67 obtained during and after GBP surgery were stained with H-E or with antibodies against p-eIF2α (green) or Grp78 (red). Nuclei are stained with DAPI (blue). The top panel illustrates severe steatosis in the pre-GBP sample and marked reduction after GBP. Staining is particularly dense around the lipid droplets (black in the stained samples). Quantification of staining is presented as relative intensity of fluorescence in pre- and post-GBP sections. *P < 0.01. (Please see http://dx.doi.org/10.2337/db08-1220 for a high-quality digital representation of this figure.)CC BY-NC-ND · PubMed Central

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Metadata

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
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
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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