Cited by 148Adipokines, Inflammation, and Metabolic DiseasesBariatric Surgery and OutcomesAdipose Tissue and Metabolism

The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.

Obesogenic memory can confer long-term increases in adipose tissue but not liver inflammation and insulin resistance after weight loss

Open access

Abstract

OBJECTIVE: Obesity represents a major risk factor for the development of type 2 diabetes mellitus, atherosclerosis and certain cancer entities. Treatment of obesity is hindered by the long-term maintenance of initially reduced body weight, and it remains unclear whether all pathologies associated with obesity are fully reversible even upon successfully maintained weight loss. METHODS: We compared high fat diet-fed, weight reduced and lean mice in terms of body weight development, adipose tissue and liver insulin sensitivity as well as inflammatory gene expression. Moreover, we assessed similar parameters in a human cohort before and after bariatric surgery. RESULTS: Compared to lean animals, mice that demonstrated successful weight reduction showed increased weight gain following exposure to ad libitum control diet. However, pair-feeding weight-reduced mice with lean controls efficiently stabilized body weight, indicating that hyperphagia was the predominant cause for the observed weight regain. Additionally, whereas glucose tolerance improved rapidly after weight loss, systemic insulin resistance was retained and ameliorated only upon prolonged pair-feeding. Weight loss enhanced insulin action and resolved pro-inflammatory gene expression exclusively in the liver, whereas visceral adipose tissue displayed no significant improvement of metabolic and inflammatory parameters compared to obese mice. Similarly, bariatric surgery in humans (n = 55) resulted in massive weight reduction, improved hepatic inflammation and systemic glucose homeostasis, while adipose tissue inflammation remained unaffected and adipocyte-autonomous insulin action only exhibit minor improvements in a subgroup of patients (42%). CONCLUSIONS: These results demonstrate that although sustained weight loss improves systemic glucose homeostasis, primarily through improved inflammation and insulin action in liver, a remarkable obesogenic memory can confer long-term increases in adipose tissue inflammation and insulin resistance in mice as well as in a significant subpopulation of obese patients.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.molmet.2015.12.001

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 Weight regain after successful weight reduction. (A) Experimental set up (B) Body weight curve (n = 16 (LFD), 7 (HFD), 10 (WR ad lib), 11 (WR pair)) (C) Lean mass after weight loss TP 1 (n = 17 (LFD), 11 (HFD), 16 (WR)) (D) Fat mass after weight loss TP 1 (n = 17 (LFD), 11 (HFD), 16 (WR)) (E) Lean after weight regain TP 2 (n = 13 (LFD), 7 (HFD), 10 (WR ad lib), 11 (WR pair)) (F) Body fat after weight regain TP 2 (n = 13 (LFD), 7 (HFD), 10 (WR ad lib), 11 (WR pair)) (G) Serum leptin levels after weight loss TP 1 (n = 8 (LFD), 7 (HFD), 8 (WR)) (H) Serum leptin levels after weight regain TP 2 (n = 13 (LFD), 7 (HFD), 10 (WR ad lib), 11 (WR pair)). §, * p < 0.05; §§, ** p < 0.01; §§§§, ****, #### p < 0.0001; (B) 2-Way-ANOVA with Bonferroni's post-test (C)–(H) 2-Way-ANOVA with Bonferroni's post-test, level of significance always compared to LFD group unless stated otherwise.
Figure 1 Weight regain after successful weight reduction. (A) Experimental set up (B) Body weight curve (n = 16 (LFD), 7 (HFD), 10 (WR ad lib), 11 (WR pair)) (C) Lean mass after weight loss TP 1 (n = 17 (LFD), 11 (HFD), 16 (WR)) (D) Fat mass after weight loss TP 1 (n = 17 (LFD), 11 (HFD), 16 (WR)) (E) Lean after weight regain TP 2 (n = 13 (LFD), 7 (HFD), 10 (WR ad lib), 11 (WR pair)) (F) Body fat after weight regain TP 2 (n = 13 (LFD), 7 (HFD), 10 (WR ad lib), 11 (WR pair)) (G) Serum leptin levels after weight loss TP 1 (n = 8 (LFD), 7 (HFD), 8 (WR)) (H) Serum leptin levels after weight regain TP 2 (n = 13 (LFD), 7 (HFD), 10 (WR ad lib), 11 (WR pair)). §, * p < 0.05; §§, ** p < 0.01; §§§§, ****, #### p < 0.0001; (B) 2-Way-ANOVA with Bonferroni's post-test (C)–(H) 2-Way-ANOVA with Bonferroni's post-test, level of significance always compared to LFD group unless stated otherwise.CC BY-NC-ND · PubMed Central
Figure 2 Insulin and glucose tolerance after weight reduction and regain. (A) Glucose tolerance after weight loss TP 1 (n = 16 (LFD), 10 (HFD), 15 (WR)) (B) Insulin tolerance after weight loss TP 1 (n = 15 (LFD), 14 (HFD), 15 (WR)) (C) Glucose tolerance after weight regain TP 2 (n = 12 (LFD), 8 (HFD), 10 (WR ad lib), 11 (WR pair)) (D) Insulin tolerance after weight regain TP 2 (n = 12 (LFD), 10 (HFD), 9 (WR ad lib), 11 (WR pair)). *, #, § p < 0.05; **, ##, §§ p < 0.01; ***, ###, §§§ p < 0.001; ****, #### p < 0.0001; 2-Way-ANOVA with Bonferroni's post-test, significance always compared to LFD group.
Figure 2 Insulin and glucose tolerance after weight reduction and regain. (A) Glucose tolerance after weight loss TP 1 (n = 16 (LFD), 10 (HFD), 15 (WR)) (B) Insulin tolerance after weight loss TP 1 (n = 15 (LFD), 14 (HFD), 15 (WR)) (C) Glucose tolerance after weight regain TP 2 (n = 12 (LFD), 8 (HFD), 10 (WR ad lib), 11 (WR pair)) (D) Insulin tolerance after weight regain TP 2 (n = 12 (LFD), 10 (HFD), 9 (WR ad lib), 11 (WR pair)). *, #, § p < 0.05; **, ##, §§ p < 0.01; ***, ###, §§§ p < 0.001; ****, #### p < 0.0001; 2-Way-ANOVA with Bonferroni's post-test, significance always compared to LFD group.CC BY-NC-ND · PubMed Central
Figure 3 Insulin secretion and pancreatic beta-cell islets after weight loss. (A) Fasted serum insulin levels TP 1 (n = 7 (LFD), 7 (HFD), 8 (WR)) (B) Fasted serum insulin levels TP 2 (n = 5 (LFD), 7 (HFD), 6 (WR ad lib), 7 (WR pair)) (C) Glucose stimulated insulin secretion after weight loss TP 1 (n = 7 (LFD), 7 (HFD), 8 (WR)) (D) Glucose stimulated insulin secretion after weight regain TP 2 (n = 5 (LFD), 7 (HFD), 6 (WR ad lib), 7 (WR pair)) (E) Area of pancreatic beta-cells relative to total pancreatic area TP 2 (n = 5 (LFD), 4 (HFD), 5 (WR ad lib), 5 (WR pair)) (F) Insulin peroxidase immunohistochemistry of the pancreas (images are representative for each group). *, §, # p < 0.05; **, §§, ## p < 0.01; *** p < 0.001; **** p < 0.0001; (C)–(D) 2-Way-ANOVA with Bonferroni's post-test, (A), (B) & (E) 1-Way-ANOVA with Bonferroni's post-test, level of significance always compared to LFD group unless displayed otherwise.
Figure 3 Insulin secretion and pancreatic beta-cell islets after weight loss. (A) Fasted serum insulin levels TP 1 (n = 7 (LFD), 7 (HFD), 8 (WR)) (B) Fasted serum insulin levels TP 2 (n = 5 (LFD), 7 (HFD), 6 (WR ad lib), 7 (WR pair)) (C) Glucose stimulated insulin secretion after weight loss TP 1 (n = 7 (LFD), 7 (HFD), 8 (WR)) (D) Glucose stimulated insulin secretion after weight regain TP 2 (n = 5 (LFD), 7 (HFD), 6 (WR ad lib), 7 (WR pair)) (E) Area of pancreatic beta-cells relative to total pancreatic area TP 2 (n = 5 (LFD), 4 (HFD), 5 (WR ad lib), 5 (WR pair)) (F) Insulin peroxidase immunohistochemistry of the pancreas (images are representative for each group). *, §, # p < 0.05; **, §§, ## p < 0.01; *** p < 0.001; **** p < 0.0001; (C)–(D) 2-Way-ANOVA with Bonferroni's post-test, (A), (B) & (E) 1-Way-ANOVA with Bonferroni's post-test, level of significance always compared to LFD group unless displayed otherwise.CC BY-NC-ND · PubMed Central
Figure 4 Tissue specific persistence of insulin resistance after weight loss and regain. (A) AKT S473 phosphorylation relative to total AKT after insulin stimulation in liver tissue (n = 4 (LFD), 4 (HFD), 4 (WR ad lib), 4 (WR pair)) (B) AKT S473 phosphorylation relative to total AKT after insulin stimulation in WAT (n = 4 (LFD), 4 (HFD), 4 (WR ad lib), 4 (WR pair)). #, § p < 0.05; ** p < 0.01, *** p < 0.0001, ****, §§§§, #### p < 0.00001; 1-Way-ANOVA with Bonferroni's post-test.
Figure 4 Tissue specific persistence of insulin resistance after weight loss and regain. (A) AKT S473 phosphorylation relative to total AKT after insulin stimulation in liver tissue (n = 4 (LFD), 4 (HFD), 4 (WR ad lib), 4 (WR pair)) (B) AKT S473 phosphorylation relative to total AKT after insulin stimulation in WAT (n = 4 (LFD), 4 (HFD), 4 (WR ad lib), 4 (WR pair)). #, § p < 0.05; ** p < 0.01, *** p < 0.0001, ****, §§§§, #### p < 0.00001; 1-Way-ANOVA with Bonferroni's post-test.CC BY-NC-ND · PubMed Central
Figure 5 Inflammation of adipose tissue persists after weight loss. (A) Crown like structures in white adipose tissue relative to total adipocytes after weight loss TP 1 (n = 7 (LFD), 7 (HFD), 8 (WR)) (B) Crown like structures in white adipose tissue relative to total adipocytes after weight regain TP 2 (n = 6 (LFD), 7 (HFD), 4 (WR ad lib), 7 (WR pair)) (C) Immunohistochemical staining of F4/80 positive cell in white adipose tissue after weight regain TP 2 (images representative for each group) (D) Average adipocytes size TP 2 (n = 6 (LFD), 7 (HFD), 5 (WR ad lib), 7 (WR pair)) (E) Adipocyte-size distribution TP 2 (n = 6 (LFD), 7 (HFD), 5 (WR ad lib), 7 (WR pair)) (F) Quantitative RT-PCR analysis of gene expression in WAT and liver TP 1 (n = 6–8 in each group)) (G) Quantitative RT-PCR analysis of gene expression in WAT and liver TP 2 (n = 6–8 in each group). *, #, § p < 0.05; **, ## p < 0.01; ***, ###, §§§ p < 0.001; 1-Way-ANOVA with Bonferroni's post-test.
Figure 5 Inflammation of adipose tissue persists after weight loss. (A) Crown like structures in white adipose tissue relative to total adipocytes after weight loss TP 1 (n = 7 (LFD), 7 (HFD), 8 (WR)) (B) Crown like structures in white adipose tissue relative to total adipocytes after weight regain TP 2 (n = 6 (LFD), 7 (HFD), 4 (WR ad lib), 7 (WR pair)) (C) Immunohistochemical staining of F4/80 positive cell in white adipose tissue after weight regain TP 2 (images representative for each group) (D) Average adipocytes size TP 2 (n = 6 (LFD), 7 (HFD), 5 (WR ad lib), 7 (WR pair)) (E) Adipocyte-size distribution TP 2 (n = 6 (LFD), 7 (HFD), 5 (WR ad lib), 7 (WR pair)) (F) Quantitative RT-PCR analysis of gene expression in WAT and liver TP 1 (n = 6–8 in each group)) (G) Quantitative RT-PCR analysis of gene expression in WAT and liver TP 2 (n = 6–8 in each group). *, #, § p < 0.05; **, ## p < 0.01; ***, ###, §§§ p < 0.001; 1-Way-ANOVA with Bonferroni's post-test.CC BY-NC-ND · PubMed Central
Figure 6 Differential regulation of inflammation in liver and WAT upon prolonged weight loss in humans. (A) Hyperinsulinemic euglycemic clamp in non-responders before and 1 year after bariatric surgery induced weight loss (n = 11) (B) Quantitative RT-PCR analysis of gene expression in liver of non-responders before and 1 year after bariatric surgery (n = 23) (C) Adipocyte size of non-responders WAT before and 1 year after bariatric surgery (n = 23) (D)) Crown like structures in WAT of non-responders before and 1 year after bariatric surgery (n = 23) (E) Quantitative RT-PCR analysis of gene expression in WAT of non-responders before and 1 year after bariatric surgery (n = 23) (F) Insulin stimulated Glucose uptake into isolated omental adipocytes (non responders: n = 23; responders: n = 32). * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001 paired student's t-test; #### p < 0.0001 unpaired student's t-test.
Figure 6 Differential regulation of inflammation in liver and WAT upon prolonged weight loss in humans. (A) Hyperinsulinemic euglycemic clamp in non-responders before and 1 year after bariatric surgery induced weight loss (n = 11) (B) Quantitative RT-PCR analysis of gene expression in liver of non-responders before and 1 year after bariatric surgery (n = 23) (C) Adipocyte size of non-responders WAT before and 1 year after bariatric surgery (n = 23) (D)) Crown like structures in WAT of non-responders before and 1 year after bariatric surgery (n = 23) (E) Quantitative RT-PCR analysis of gene expression in WAT of non-responders before and 1 year after bariatric surgery (n = 23) (F) Insulin stimulated Glucose uptake into isolated omental adipocytes (non responders: n = 23; responders: n = 32). * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001 paired student's t-test; #### p < 0.0001 unpaired student's t-test.CC BY-NC-ND · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 48 references

Cited by

Sorted by citations

See all 148

Metadata

Authors
Schmitz, J., Evers, N., Awazawa, M., Nicholls, H. T., Brönneke, H. S., Dietrich, A., Mauer, J., Blüher, M., & Brüning, J. C.
Affiliations
  • University of Cologne (DE)
  • Leipzig University (DE)
Corresponding author
Brüning, J.C.
Venue
Molecular Metabolism
Publisher
Elsevier BV
Published
2016-05
Volume
5
Issue
5
Pages
328-339
ISSN
2212-8778 (ISSN-L)
OpenAlex
W2239531983
Cited by
148
References
48
Citations by year
2026: 22 · 2025: 17 · 2024: 17 · 2023: 16 · 2022: 13 · 2021: 14 · 2020: 15 · 2019: 12 · 2018: 8 · 2017: 10 · 2016: 4
FWCI
10.62
Type
journal article
Language
en
Open access
Locations
  • Molecular Metabolism (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
  • Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
Keywords
weight regain, weight loss, insulin resistance, liver inflammation, adipose tissue inflammation, hyperphagia, pair feeding, bariatric surgery, glucose homeostasis, type 2 diabetes, visceral adipose tissue, high-fat diet

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