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Cited by 101Liver Disease Diagnosis and TreatmentPeroxisome Proliferator-Activated ReceptorsLiver Diseases and Immunity

PPAR‐γ‐induced changes in visceral fat and adiponectin levels are associated with improvement of steatohepatitis in patients with NASH

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Gastaldelli, Amalia, Sabatini, Silvia, Carli, Fabrizia, Gaggini, Melania, Bril, Fernando, Belfort‐DeAguiar, Renata, Positano, Vincenzo, Barb, Diana +3 more·2021·Liver International
DOI 10.1111/liv.15005PMC PMC9290929
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Abstract

BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor (PPAR)-γ agonists decrease hepatic/visceral fat (VF) and improve necroinflammation despite subcutaneous (SC) fat weight-gain. Understanding the impact of changes in VF, VF-to-SC fat distribution (VF/SC) and adiponectin (ADPN) levels in relation to histological improvement after weight-loss or pioglitazone is relevant as novel PPAR-γ agonists are being developed for treating non-alcoholic steatohepatitis (NASH). METHODS: Fifty-five patients with NASH received a -500 kcal/d hypocaloric diet and were randomized (double-blind) to pioglitazone (45 mg/d) or placebo for 6-months. Before and after treatment patients underwent a liver biopsy and measurement of hepatic/peripheral glucose fluxes, hepatic/adipose tissue-IR and, in 35 patients, hepatic and VF/SC-fat was measured by magnetic resonance spectroscopy/imaging. Data were examined by multivariable statistical analyses combined with machine-learning techniques (partial least square discriminant analysis [PLS-DA]). RESULTS: Both pioglitazone (despite weight-gain) and placebo (if weight-loss) reduced steatosis but only pioglitazone ameliorated necroinflammation. Using machine-learning PLS-DA showed that the treatment differences induced by a PPAR-γ agonist vs placebo on metabolic variables and liver histology could be best explained by the increase in ADPN and a decrease in VF/SC, and to a lesser degree, improvement in oral glucose tolerance test-glucose concentrations and ALT. Decrease in steatosis and disease activity score (ballooning plus lobular inflammation) kept a close relationship with an increase in ADPN (r = -.71 and r = -.44, P < .007, respectively) and reduction in VF/SC fat (r = .41 and r = .37, P < .03 respectively). CONCLUSIONS: Reduction in VF and improved VF/SC-distribution, combined with an increase in ADPN, mediate the histological benefits of PPAR-γ action, highlighting the central role of fat metabolism and its distribution on steatohepatitis disease activity in patients with NASH.

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  • By augmenting WAT expandability, PPARγ activation redirects NEFA from liver and skeletal muscle to subcutaneous fat depots and reduces chronic adipose tissue as well as systemic inflammation but also organ lipotoxicity and insulin resistance.

    “By augmenting WAT expandability, PPARγ activation redirects NEFA from liver and skeletal muscle to subcutaneous fat depots and reduces chronic adipose tissue as well as systemic inflammation but also organ lipotoxicity and insulin resistance [175].”

    From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [175]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • PPARγ is highly expressed in WAT and controls NEFA uptake, lipogenesis and adipocyte differentiation.

    “PPARγ is highly expressed in WAT and controls NEFA uptake, lipogenesis as well as adipocyte differentiation [171].”

    From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [171]

    The Introduction (page unavailable) reports increased formation of new adipocytes during pioglitazone treatment, which offers limited support for the differentiation part of the claim. The Discussion (page unavailable) describes reduced lipolysis with PPAR-γ agonists, but our copy does not state that PPARγ is highly expressed in white adipose tissue or that it controls NEFA uptake and lipogenesis. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

  • Pioglitazone has been consistently associated with reduced risk of myocardial infarction and ischemic stroke both in primary and secondary prevention, despite increased risk of hospitalization for heart failure due to fluid retention.

    “Of note, despite the increased risk of hospitalization for heart failure due to fluid retention, pioglitazone has been consistently associated with reduced risk of myocardial infarction and ischemic stroke both in primary and secondary prevention [175].”

    From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [175]

    The Methods and Results (page numbers unavailable) examine pioglitazone in patients with NASH, focusing on liver fat, visceral fat, and metabolic measures. Searches for myocardial infarction, ischemic stroke, primary or secondary prevention, and heart-failure hospitalization found no passage addressing the claimed cardiovascular benefits or risk. (LLM, conf=0.76)

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Cited by

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Authors
Gastaldelli, A., Sabatini, S., Carli, F., Gaggini, M., Bril, F., Belfort‐DeAguiar, R., Positano, V., Barb, D., Kadiyala, S., Harrison, S., & Cusi, K.
Affiliations
  • The University of Texas at San Antonio Health Science Center (US)
  • University of Siena (IT)
  • Istituto di Fisiologia Clinica (IT)
  • University of Florida Health (US)
  • Yale University (US)
  • Fondazione Toscana Gabriele Monasterio (IT)
  • Pinnacle Clinical Research (US)
Corresponding author
  • Gastaldelli, Amalia
  • Cusi, Kenneth
ORCID
Venue
Liver International
Publisher
Wiley
Published
2021-07-21
Volume
41
Issue
11
Pages
2659-2670
ISSN
  • 0106-9543 (ISSN-L)
  • 1478-3223
  • 1478-3231
DOI
10.1111/liv.15005
PMC
PMC9290929
OpenAlex
W3181783841
Cited by
101
References
12
Citations by year
2026: 16 · 2025: 13 · 2024: 27 · 2023: 19 · 2022: 20 · 2021: 6
FWCI
12.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Liver International (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Consiglio Nazionale delle Ricerche (DSB.AD003.061)
  • H2020 Health (634413)
  • H2020 Marie Skłodowska-Curie Actions (722619, 734719)
  • Takeda Pharmaceuticals U.S.A.
  • National Center for Research Resources (MO1‐RR‐01346)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords
nonalcoholic steatohepatitis, PPARγ agonists, pioglitazone, visceral fat, adiponectin, visceral-to-subcutaneous fat ratio, hepatic steatosis, hepatic necroinflammation, hypocaloric diet, insulin resistance, body fat distribution, liver histopathology
MeSH terms
Diet, Reducing, Humans, Hypoglycemic Agents, Insulin Resistance, Liver, Obesity, Thiazolidinediones, PPAR gamma, Intra-Abdominal Fat, Adiponectin, Non-alcoholic Fatty Liver Disease

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