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Cited by 61Lipid metabolism and disordersExercise and Physiological ResponsesCardiovascular and exercise physiology

Angiopoietin-like protein 4 is an exercise-induced hepatokine in humans, regulated by glucagon and cAMP

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Ingerslev, Bodil, Hansen, Jakob S., Hoffmann, Christoph, Clemmesen, Jens O., Secher, Niels H., Scheler, Mika, Hrabĕ de Angelis, Martin, Häring, Hans U. +3 more·2017·Molecular Metabolism
DOI 10.1016/j.molmet.2017.06.018PMC PMC5641605
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Abstract

OBJECTIVE: Angiopoietin-like protein-4 (ANGPTL4) is a circulating protein that is highly expressed in liver and implicated in regulation of plasma triglyceride levels. Systemic ANGPTL4 increases during prolonged fasting and is suggested to be secreted from skeletal muscle following exercise. METHODS: We investigated the origin of exercise-induced ANGPTL4 in humans by measuring the arterial-to-venous difference over the leg and the hepato-splanchnic bed during an acute bout of exercise. Furthermore, the impact of the glucagon-to-insulin ratio on plasma ANGPTL4 was studied in healthy individuals. The regulation of ANGPTL4 was investigated in both hepatic and muscle cells. RESULTS: The hepato-splanchnic bed, but not the leg, contributed to exercise-induced plasma ANGPTL4. Further studies using hormone infusions revealed that the glucagon-to-insulin ratio is an important regulator of plasma ANGPTL4 as elevated glucagon in the absence of elevated insulin increased plasma ANGPTL4 in resting subjects, whereas infusion of somatostatin during exercise blunted the increase of both glucagon and ANGPTL4. Moreover, activation of the cAMP/PKA signaling cascade let to an increase in ANGPTL4 mRNA levels in hepatic cells, which was prevented by inhibition of PKA. In humans, muscle ANGPTL4 mRNA increased during fasting, with only a marginal further induction by exercise. In human muscle cells, no inhibitory effect of AMPK activation could be demonstrated on ANGPTL4 expression. CONCLUSIONS: The data suggest that exercise-induced ANGPTL4 is secreted from the liver and driven by a glucagon-cAMP-PKA pathway in humans. These findings link the liver, insulin/glucagon, and lipid metabolism together, which could implicate a role of ANGPTL4 in metabolic diseases.

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Crossref · 10.1016/j.molmet.2017.06.018

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  • Plasma ANGPTL4 acts on myotubes and is well-established as a myokine derived from physical exercise (exercise factor).

    “Specifically, plasma ANGPTL4 acts on myotubes, and is well-established as a myokine derived from physical exercise (exercise factor; Raschke and Eckel, 2013; Ingerslev et al., 2017).”

    From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Ingerslev et al., 2017

    The Discussion reports that during exercise ANGPTL4 was released from the liver, while the leg did not contribute to circulating ANGPTL4; it identifies the protein as an exercise-regulated hepatokine, contrary to the claim that plasma ANGPTL4 is an established exercise-derived myokine. The Discussion mentions ANGPTL4 release from stimulated human myotubes, but does not show plasma ANGPTL4 acting on myotubes. Page numbers are unavailable in our copy. (LLM, conf=0.90)

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  • ANGPTL4 secretion by the liver is primarily regulated during exercise bouts, following 3 h of ergometer cycling at 50% VO2 max, in response to increased glucagon-to-insulin ratio.

    “Angiopoietin-like 4 (ANGPTL4) secretion by the liver has been primarily regulated during exercise bouts, following 3 h of ergometer cycling at 50% VO2 max, in response to increased glucagon-to-insulin ratio [170], and therefore its endocrine role is hypothesized [3].”

    From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [170]

    The Discussion and Conclusion identify the hepato-splanchnic bed as a source of exercise-induced circulating ANGPTL4 and the glucagon-to-insulin ratio as an important regulator. However, the Methods describe 3 h of cycling at 50% VO2 max as a separate exercise-versus-fasting protocol; the hepatic-release measurements followed 2 h of cycling at 60% VO2 max, with release detected during recovery. The claim conflates those protocols and places the liver-release finding during exercise rather than recovery. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • ANGPTL proteins are secreted by adipose tissue, skeletal muscle, intestinal, and liver cells and are responsible for energy metabolism, TG turnover modulation in adipose tissue, and regulation of blood glucose levels.

    “Angiopoietin-like protein (ANGPTL) is a group of proteins that can be secreted by the AT, SkM, intestinal, and liver cells and is responsible for several processes, among them energy metabolism, and TG turnover modulation in AT and the regulation of blood glucose levels (Ingerslev et al., 2017; Popova et al., 2018).”

    From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Ingerslev et al., 2017

    The Introduction says ANGPTL4 is expressed in adipose tissue, intestine, skeletal muscle and liver, and describes effects on triglycerides and a suggested improvement in glucose tolerance. But the paper concerns ANGPTL4 specifically, not ANGPTL proteins as a group; its Discussion reports exercise-induced secretion from the liver, not established secretion from all four tissues. It also does not establish regulation of blood glucose levels as stated. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • ANGPTL is regulated through PPAR and can regulate serum triglyceride levels by increasing lipoprotein lipase activity, promoting lipolysis in adipose tissue, and improving glucose tolerance.

    “ANGPTL is regulated through peroxisome proliferator-activated receptor (PPAR) and has the ability to regulate serum triglyceride levels. This ability is related to increased lipoprotein lipase (LPL) activity, promoting lipolysis in AT, and improving glucose tolerance (Ingerslev et al., 2017).”

    From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Ingerslev et al., 2017

    The Introduction supports PPAR regulation, triglyceride regulation, and promotion of adipose-tissue lipolysis. But it says ANGPTL4 decreases—not increases—LPL activity, and only suggests that it improves glucose tolerance. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Fasting combined with physical exercise is an important inducer of ANGPTL4 expression.

    “The practice of fasting combined with physical exercise is indicated as an important inducer of ANGPTL4 expression”

    From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Ingerslev et al., 2017

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Authors
Ingerslev, B., Hansen, J. S., Hoffmann, C., Clemmesen, J. O., Secher, N. H., Scheler, M., Hrabĕ de Angelis, M., Häring, H. U., Pedersen, B. K., Weigert, C., & Plomgaard, P.
Affiliations
  • Copenhagen University Hospital (DK)
  • University of Tübingen (DE)
  • Helmholtz Munich (DE)
Corresponding author
Plomgaard, Peter
ORCID
Venue
Molecular Metabolism
Publisher
Elsevier BV
Published
2017-10
Volume
6
Issue
10
Pages
1286-1295
ISSN
2212-8778 (ISSN-L)
DOI
10.1016/j.molmet.2017.06.018
PMC
PMC5641605
OpenAlex
W2734285800
Cited by
61
References
47
Citations by year
2026: 3 · 2025: 5 · 2024: 8 · 2023: 7 · 2022: 11 · 2021: 6 · 2020: 8 · 2019: 7 · 2018: 6
FWCI
4.44
Type
journal article
Language
en
Open access
Licence
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)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • mediaTUM (Technical University of Munich) (submittedVersion, cc-by)
  • Site cant be reached (submittedVersion, cc-by)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
Funders
  • TrygFonden
  • Danish Diabetes Academy
  • Novo Nordisk Fonden
  • Danmarks Grundforskningsfond (DNRF55)
  • Bundesministerium für Bildung und Forschung
  • Augustinus Fonden
  • Fonden til Lægevidenskabens Fremme
  • Strategiske Forskningsråd (09-067009, 09-075724)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
  • Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
Keywords
ANGPTL4, hepatokines, physical activity, glucagon, cAMP/PKA signaling, hepatic lipid metabolism, somatostatin, AMPK, skeletal muscle, fasting, plasma triglycerides
MeSH terms
Angiopoietin-Like Protein 4, Cyclic AMP, Cells, Cultured, Glucagon, Humans, Insulin, Liver, Male, RNA, Messenger, Exercise, Muscle, Skeletal, Muscle Cells, Angiopoietins, Young Adult

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