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Cited by 178Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesHypothalamic control of reproductive hormones

Inter‐organ communication: a gatekeeper for metabolic health

Open access
Castillo‐Armengol, Judit, Fajas, Lluis, Lopez‐Mejia, Isabel C·2019·The EMBO Reports
DOI 10.15252/embr.201947903PMC PMC6726901
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Abstract

Multidirectional interactions between metabolic organs in the periphery and the central nervous system have evolved concomitantly with multicellular organisms to maintain whole‐body energy homeostasis and ensure the organism's adaptation to external cues. These interactions are altered in pathological conditions such as obesity and type 2 diabetes. Bioactive peptides and proteins, such as hormones and cytokines, produced by both peripheral organs and the central nervous system, are key messengers in this inter‐organ communication. Despite the early discovery of the first hormones more than 100 years ago, recent studies taking advantage of novel technologies have shed light on the multiple ways used by cells in the body to communicate and maintain energy balance. This review briefly summarizes well‐established concepts and focuses on recent advances describing how specific proteins and peptides mediate the crosstalk between gut, brain, and other peripheral metabolic organs in order to maintain energy homeostasis. Additionally, this review outlines how the improved knowledge about these inter‐organ networks is helping us to redefine therapeutic strategies in an effort to promote healthy living and fight metabolic disorders and other diseases.

AI snapshot

Written from the paper’s full text.

TL;DR

This review describes how hormones, cytokines, myokines, adipokines, and neural signals coordinate gut, brain, liver, muscle, adipose, and pancreas to maintain energy homeostasis in feeding, fasting, cold exposure, and exercise. It also summarizes how these inter-organ networks are altered in obesity and type 2 diabetes and discusses therapeutic strategies, especially GLP-1 receptor agonists.

Key findings

  • In feeding, gut hormones such as GLP-1, secretin, and LEAP2 signal to the brain to reduce food intake; GLP-1 and GIP potentiate glucose-stimulated insulin secretion; FGF19 represses hepatic bile acid synthesis; and leptin suppresses food intake. In fasting, ghrelin increases appetite and adiposity, asprosin promotes hepatic glucose production and food intake, FGF21 increases adipose lipolysis and hepatic fatty acid oxidation/ketogenesis, and glucagon drives glycogenolysis and gluconeogenesis.
  • Cold-induced thermogenesis involves hypothalamic orexin/BMP8b, sympathetic norepinephrine, thyroid hormones, FGF21, and bile acids acting on brown adipose tissue; a UCP1-independent pathway mediated by PM20D1 is also described. Exercise-induced IL-6, irisin, and cathepsin B mediate muscle crosstalk with pancreas, liver, adipose tissue, and brain.
  • In obesity and related disorders, inter-organ communication is altered: leptin resistance, increased NPY, decreased adiponectin, increased FGF21 and asprosin, ghrelin resistance, altered GLP-1 after bariatric surgery, and proinflammatory adipokines are reported. The review notes that in pathological situations WAT can account for more than 50% of human body weight.
  • Therapeutic efforts include GLP-1 receptor agonists, which promote satiety and reduce food intake; leptin therapy alone failed to induce significant weight loss or insulin sensitization; FGF21 variants showed only a small trend toward glucose lowering in humans; and an asprosin-neutralizing antibody reduced appetite, body weight, and blood glucose in obese mice. The review also states that more than 15% of the protein-coding genome encodes roughly 3,000 secreted proteins, but only a handful have been properly annotated.

Methods

  • Design: narrative review summarizing well-established concepts and recent advances in inter-organ communication.
  • Data or sample: Not stated in the paper; no primary dataset or systematic sample is reported. The review synthesizes cited literature and includes figures and a table.
  • Main analysis: qualitative synthesis organized by physiological states—feeding/fasting cycles, non-shivering thermogenesis, exercise, and obesity—and by therapeutic implications.

Limitations

  • Stated: the review explicitly excludes the role of the immune system in energy homeostasis, noting it has been discussed elsewhere. It also identifies unresolved or controversial areas, including the role of FGF21, the normal physiology of Lcn5 and Metrnl, and the central mechanism of ghrelin action.
  • Evident: as a narrative review, it does not report a systematic search strategy, inclusion criteria, quality assessment, or meta-analysis.
  • Evident: therapeutic conclusions rely on cited preclinical and early clinical studies and are not systematically appraised.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.15252/embr.201947903

Cites

175 of 175 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation

    Peripheral organs and immune cells can produce cytokines that participate in inter-organ communication.

    “Peripheral organs and immune cells can also produce smaller bioactive proteins, namely cytokines 1, that also participate in inter‐organ communication.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Dinarello CA (2007) Historical insights into cytokines. Eur J Immunol 37(Suppl 1): S34–S45 source

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  • Premisecitation

    Secretin can inhibit food intake via activation of secretin receptor in vagal sensory nerves and melanocortin signaling in the brain.

    “Moreover, secretin can also inhibit food intake via the activation of secretin receptor (SctR) in vagal sensory nerves and melanocortin signaling in the brain 22, 23.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Cheng CY, Chu JY, Chow BK (2011) Central and peripheral administration of secretin inhibits food intake in mice through the activation of the melanocortin system. Neuropsychopharmacology 36: 459–471 source

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    • cites [23] Chu JY, Cheng CY, Sekar R, Chow BK (2013) Vagal afferent mediates the anorectic effect of peripheral secretin. PLoS One 8: e64859 source

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  • Premisecitation

    A major target for gut-derived hormones is the vagal afferent neurons (VANs).

    “A major target for gut‐derived hormones is the vagal afferent neurons (VANs) 21.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Ronveaux CC, Tome D, Raybould HE (2015) Glucagon‐like peptide 1 interacts with ghrelin and leptin to regulate glucose metabolism and food intake through vagal afferent neuron signaling. J Nutr 145: 672–680 source

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  • Premisecitation

    An increase in circulating glucose levels is sensed by pancreatic β-cells through the glucose transporter GLUT2.

    “An increase in circulating glucose levels is sensed by pancreatic β‐cells through the glucose transporter GLUT2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Tokarz VL, MacDonald PE, Klip A (2018) The cell biology of systemic insulin function. J Cell Biol 217: 2273–2289 source

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  • Premisecitation

    GLP-1 and GIP work synergistically to potentiate glucose-stimulated insulin secretion by pancreatic β-cells.

    “GLP‐1 and GIP work synergistically to potentiate glucose‐stimulated insulin secretion by pancreatic β‐cells 21.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Ronveaux CC, Tome D, Raybould HE (2015) Glucagon‐like peptide 1 interacts with ghrelin and leptin to regulate glucose metabolism and food intake through vagal afferent neuron signaling. J Nutr 145: 672–680 source

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    Premisecitation

    Enteroendocrine cells sense nutrients in the intestinal lumen and produce CCK, secretin, GIP, and GLP-1.

    “Enteroendocrine cells sense nutrients in the intestinal lumen and produce peptides such as cholecystokinin (CCK), secretin, and the incretins; glucose‐dependent insulinotropic peptide (GIP); and glucagon‐like peptide 1 (GLP‐1) 19, 20.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA et al (2002) Gut hormone PYY(3‐36) physiologically inhibits food intake. Nature 418: 650–654 source

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    • cites [20] Turton MD, O'Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, Choi SJ, Taylor GM, Heath MM, Lambert PD et al (1996) A role for glucagon‐like peptide‐1 in the central regulation of feeding. Nature 379: 69–72 source

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    Premisecitation

    The nervous system coordinates whole-body metabolism by producing neurohormones that act locally and by direct innervation of target tissues.

    “Alternatively, the nervous system coordinates whole‐body metabolism not only by the production of neurohormones that act locally, but also by direct innervation of the target tissues 2, 3, 4, 5.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Ryan DG, Murphy MP, Frezza C, Prag HA, Chouchani ET, O'Neill LA, Mills EL (2019) Coupling Krebs cycle metabolites to signalling in immunity and cancer. Nat Metab 1: 16–33 source

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    • cites [3] Myers Jr MG, Olson DP (2012) Central nervous system control of metabolism. Nature 491: 357–363 source

      Not checked in the free run.

    • cites [4] Nogueiras R, Tschop MH, Zigman JM (2008) Central nervous system regulation of energy metabolism: ghrelin versus leptin. Ann N Y Acad Sci 1126: 14–19 source

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    Premisecitation

    Leptin suppresses food intake and production of adrenal corticosteroids while promoting energy expenditure and decreasing insulin secretion.

    “Indeed, leptin suppresses food intake and the production of adrenal corticosteroids while promoting energy expenditure and decreasing insulin secretion 38, 39.”
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    • cites [38] Pan WW, Myers Jr MG (2018) Leptin and the maintenance of elevated body weight. Nat Rev Neurosci 19: 95–105 source

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    • cites [39] Stern JH, Rutkowski JM, Scherer PE (2016) Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab 23: 770–784 source

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    By signaling through the brain, insulin regulates feeding behavior and modifies energy metabolism in liver and adipose tissues, as well as several more cognitive functions.

    “By signaling through the brain, insulin regulates feeding behavior and modifies energy metabolism in liver and adipose tissues, as well as several more cognitive functions 27, 28, 29, 30, 31.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Lee SH, Zabolotny JM, Huang H, Lee H, Kim YB (2016) Insulin in the nervous system and the mind: functions in metabolism, memory, and mood. Mol Metab 5: 589–601 source

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    • cites [28] Gray SM, Meijer RI, Barrett EJ (2014) Insulin regulates brain function, but how does it get there? Diabetes 63: 3992–3997 source

      Not checked in the free run.

    • cites [29] Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Muller‐Wieland D, Kahn CR (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289: 2122–2125 source

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    Intact hepatic insulin signaling is dispensable for the postprandial repression of hepatic glucose production in the absence of hepatic FoxO1, highlighting the importance of hypothalamic insulin signaling in the control of liver glucose metabolism.

    “Intact hepatic insulin signaling is, however, dispensable for the postprandial repression of hepatic glucose production in the absence of hepatic FoxO1 32, 33, highlighting the importance of hypothalamic insulin signaling in the control of liver glucose metabolism 34.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [32] O‐Sullivan I, Zhang W, Wasserman DH, Liew CW, Liu J, Paik J, DePinho RA, Stolz DB, Kahn CR, Schwartz MW et al (2015) FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization. Nat Commun 6: 7079 source

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    • cites [33] Titchenell PM, Chu Q, Monks BR, Birnbaum MJ (2015) Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo. Nat Commun 6: 7078 source

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    • cites [34] Obici S, Zhang BB, Karkanias G, Rossetti L (2002) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8: 1376–1382 source

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    Premisecitation

    FGF19 signals to the liver and induces a feedback repression of hepatic BA synthesis.

    “FGF19 then signals to the liver and induces a feedback repression of hepatic BA synthesis 42.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA et al (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2: 217–225 source

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    Premisecitation

    Leptin can activate glucose uptake in BAT, as well as glucose uptake and fatty acid oxidation in muscle in an AMPK-dependent manner.

    “Leptin can also activate glucose uptake in BAT, as well as glucose uptake and fatty acid oxidation in muscle in an AMPK‐dependent manner 40.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB (2002) Leptin stimulates fatty‐acid oxidation by activating AMP‐activated protein kinase. Nature 415: 339–343 source

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    Premisecitation

    LEAP2 can fully blunt GHSR activation by ghrelin, thus reducing food intake and growth hormone release.

    “Indeed, LEAP2 can fully blunt GHSR activation by ghrelin, thus reducing food intake and growth hormone (GH) release 47.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Ge X, Yang H, Bednarek MA, Galon‐Tilleman H, Chen P, Chen M, Lichtman JS, Wang Y, Dalmas O, Yin Y et al (2018) LEAP2 is an endogenous antagonist of the ghrelin receptor. Cell Metab 27: 461–469 e6 source

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    Premisecitation

    FGF19 increases liver protein and glycogen synthesis while repressing hepatic glucose production, independently from insulin.

    “FGF19 also increases liver protein and glycogen synthesis while repressing hepatic glucose production 43, 44, in order to ensure proper postprandial energy storage independently from insulin.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Kir S, Beddow SA, Samuel VT, Miller P, Previs SF, Suino‐Powell K, Xu HE, Shulman GI, Kliewer SA, Mangelsdorf DJ (2011) FGF19 as a postprandial, insulin‐independent activator of hepatic protein and glycogen synthesis. Science 331: 1621–1624 source

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    • cites [44] Potthoff MJ, Boney‐Montoya J, Choi M, He T, Sunny NE, Satapati S, Suino‐Powell K, Xu HE, Gerard RD, Finck BN et al (2011) FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB‐PGC‐1alpha pathway. Cell Metab 13: 729–738 source

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    Premisecitation

    Fgf15 can signal through the brain to modulate glucose homeostasis and glucagon secretion.

    “Importantly, Fgf15 can also signal through the brain to modulate glucose homeostasis 45 and glucagon secretion 46.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Ryan KK, Kohli R, Gutierrez‐Aguilar R, Gaitonde SG, Woods SC, Seeley RJ (2013) Fibroblast growth factor‐19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats. Endocrinology 154: 9–15 source

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    • cites [46] Picard A, Soyer J, Berney X, Tarussio D, Quenneville S, Jan M, Grouzmann E, Burdet F, Ibberson M, Thorens B (2016) A genetic screen identifies hypothalamic Fgf15 as a regulator of glucagon secretion. Cell Rep 17: 1795–1806 source

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    Premisecitation

    In the brain, adiponectin activates AMPK signaling in hypothalamic ARC, resulting in an increase in food intake and a reduction in energy expenditure, suggesting that in the hypothalamus adiponectin promotes feeding and inhibits the anorexigenic effects of leptin.

    “In the brain, adiponectin activates AMPK signaling in hypothalamic ARC, resulting in an increase in food intake and a reduction in energy expenditure, suggesting that in the hypothalamus adiponectin promotes feeding and inhibits the anorexigenic effects of leptin 55, 56.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [55] Steinberg GR, Kemp BE (2007) Adiponectin: starving for attention. Cell Metab 6: 3–4 source

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    • cites [56] Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, Kozono H, Takamoto I, Okamoto S, Shiuchi T et al (2007) Adiponectin stimulates AMP‐activated protein kinase in the hypothalamus and increases food intake. Cell Metab 6: 55–68 source

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    Premisecitation

    Plasma concentrations of ghrelin are high during fasting and decrease in the postprandial state.

    “Plasma concentrations of ghrelin are high during fasting and decrease in the postprandial state 48.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS (2001) A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50: 1714–1719 source

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    Premisecitation

    FGF21 was first identified as a hepatokine and is necessary for adaptation to fasting.

    “Fibroblast growth factor 21 (FGF21) was first identified as an hepatokine 61 and has been shown to be necessary for the adaptation to fasting 62, 63.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [61] Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA et al (2005) FGF‐21 as a novel metabolic regulator. J Clin Invest 115: 1627–1635 source

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    • cites [62] Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos‐Flier E (2007) Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 5: 426–437 source

      Not checked in the free run.

    • cites [63] Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V et al (2007) Endocrine regulation of the fasting response by PPARalpha‐mediated induction of fibroblast growth factor 21. Cell Metab 5: 415–425 source

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    Premisecitation

    FGF21 knockout mice exhibit lower glycemia in the fasted state, and lower plasma levels of ketone bodies in both the fasted and the fed state.

    “It is worth noting that FGF21 knockout mice exhibit lower glycemia in the fasted state, and lower plasma levels of ketone bodies in both the fasted and the fed state 64, 65.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [64] BonDurant LD, Potthoff MJ (2018) Fibroblast growth factor 21: a versatile regulator of metabolic homeostasis. Annu Rev Nutr 38: 173–196 source

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    • cites [65] Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, Mohammadi M, Finck BN, Mangelsdorf DJ, Kliewer SA et al (2009) FGF21 induces PGC‐1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci USA 106: 10853–10858 source

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    Premisecitation

    Asprosin directly targets the liver to promote glucose release, without increasing plasma levels of glucagon, catecholamines, and glucocorticoids.

    “Asprosin directly targets the liver to promote glucose release, without increasing plasma levels of glucagon, catecholamines, and glucocorticoids.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Romere C, Duerrschmid C, Bournat J, Constable P, Jain M, Xia F, Saha PK, Del Solar M, Zhu B, York B et al (2016) Asprosin, a fasting‐induced glucogenic protein hormone. Cell 165: 566–579 source

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    Premisecitation

    Asprosin's promotion of glucose release is independent from glucagon receptor signaling and from the β-adrenergic receptor.

    “This process is independent from glucagon receptor signaling and from the β‐adrenergic receptor 59.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Romere C, Duerrschmid C, Bournat J, Constable P, Jain M, Xia F, Saha PK, Del Solar M, Zhu B, York B et al (2016) Asprosin, a fasting‐induced glucogenic protein hormone. Cell 165: 566–579 source

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    Premisecitation

    In peripheral tissues, adiponectin promotes liver insulin sensitivity via several independent mechanisms: an AMPK-dependent mechanism involving increased ACC phosphorylation, an AMPK-independent mechanism involving reduction in liver ceramide levels, and an IL-6-dependent mechanism involving upregulation of IRS-2 through STAT3 activation.

    “In the peripheral tissues, adiponectin promotes liver insulin sensitivity via several independent mechanisms: an AMPK‐dependent mechanism involving increased ACC phosphorylation, an AMPK‐independent mechanism that involves a reduction in liver ceramide levels 57, and an IL‐6‐dependent mechanism that involves the upregulation of insulin receptor substrate 2 (IRS‐2) through the activation of STAT3 5”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [57] Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, Davis KE, Bikman BT, Halberg N, Rutkowski JM et al (2011) Receptor‐mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 17: 55–63 source

      Not checked in the free run.

    • cites [58] Awazawa M, Ueki K, Inabe K, Yamauchi T, Kubota N, Kaneko K, Kobayashi M, Iwane A, Sasako T, Okazaki Y et al (2011) Adiponectin enhances insulin sensitivity by increasing hepatic IRS‐2 expression via a macrophage‐derived IL‐6‐dependent pathway. Cell Metab 13: 401–412 source

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    Premisecitation

    Central administration of orexin peptide stimulates BAT activation and therefore thermogenesis.

    “The central administration of orexin peptide has been described to stimulate BAT activation and therefore thermogenesis 77.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Sellayah D, Bharaj P, Sikder D (2011) Orexin is required for brown adipose tissue development, differentiation, and function. Cell Metab 14: 478–490 source

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    Premisecitation

    BMP8b can also be produced in BAT and promote NE signaling locally, activating MAPK pathway and lipolysis in brown adipocytes.

    “Interestingly, BMP8b can also be produced in BAT and promote NE signaling locally, activating the MAPK pathway and lipolysis in brown adipocytes 80.”
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    • cites [80] Whittle AJ, Carobbio S, Martins L, Slawik M, Hondares E, Vazquez MJ, Morgan D, Csikasz RI, Gallego R, Rodriguez‐Cuenca S et al (2012) BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 149: 871–885 source

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    Premisecitation

    Mammals have BAT, a highly specialized tissue that functions to produce heat.

    “Mammals have BAT, a highly specialized tissue that functions to produce heat 73.”
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    • cites [73] Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84: 277–359 source

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    Cold is sensed by terminals of sensory neurons in skin, and this signal is processed in the hypothalamic preoptic area (POA), also known as the thermoregulatory center.

    “Cold is sensed by the terminals of sensory neurons found in skin, and this signal is then processed in the hypothalamic preoptic area (POA), also known as the thermoregulatory center 76.”
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    • cites [76] Zhang W, Bi S (2015) Hypothalamic regulation of brown adipose tissue thermogenesis and energy homeostasis. Front Endocrinol (Lausanne) 6: 136

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    WAT innervation is denser in specific regions of subcutaneous WAT and can be increased in response to cold.

    “However, it is denser in specific regions of subcutaneous (or inguinal) WAT and can be increased in response to cold 70, 71.”
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    • cites [70] Chi J, Wu Z, Choi CHJ, Nguyen L, Tegegne S, Ackerman SE, Crane A, Marchildon F, Tessier‐Lavigne M, Cohen P (2018) Three‐dimensional adipose tissue imaging reveals regional variation in beige fat biogenesis and PRDM16‐dependent sympathetic neurite density. Cell Metab 27: 226–236 e3 source

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    • cites [71] Jiang H, Ding X, Cao Y, Wang H, Zeng W (2017) Dense intra‐adipose sympathetic arborizations are essential for cold‐induced beiging of mouse white adipose tissue. Cell Metab 26: 686–692 e3 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    BAT is especially abundant in hibernating mammals, but can also be found in adult humans.

    “BAT is especially abundant in hibernating mammals 74 , but can also be found in adult humans 75.”
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    • cites [74] Gesta S, Tseng YH, Kahn CR (2007) Developmental origin of fat: tracking obesity to its source. Cell 131: 242–256 source

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    • cites [75] Cypess AM, Kahn CR (2010) Brown fat as a therapy for obesity and diabetes. Curr Opin Endocrinol Diabetes Obes 17: 143–149 source

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    Free fatty acids resulting from lipolysis are used both as energy substrates and as activators of UCP1 to uncouple ATP production from mitochondrial respiration into heat.

    “Free fatty acids, resulting from lipolysis, are used both as energy substrates and as activators of UCP1 to uncouple ATP production from mitochondrial respiration into heat 73, 85.”
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    • cites [73] Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84: 277–359 source

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    • cites [85] Fedorenko A, Lishko PV, Kirichok Y (2012) Mechanism of fatty‐acid‐dependent UCP1 uncoupling in brown fat mitochondria. Cell 151: 400–413 source

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    Under cold exposure, FGF21 can be secreted by BAT and WAT, have a paracrine effect, and stimulate the expression of thermogenic genes.

    “Under cold exposure, FGF21 can be secreted by BAT and WAT, have a paracrine effect, and stimulate the expression of thermogenic genes 91.”
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    • cites [91] Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, Villarroya F (2011) Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 286: 12983–12990 source

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    Some teams have reported that FGF21 knockout mice have impaired adaptation to chronic cold exposure and decreased browning of WAT.

    “Some teams have reported that FGF21 knockout mice have impaired adaptation to chronic cold exposure and decreased browning of WAT 92.”
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    • cites [92] Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, Wu J, Kharitonenkov A, Flier JS, Maratos‐Flier E et al (2012) FGF21 regulates PGC‐1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 26: 271–281 source

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    Brite adipocytes can express UCP1 and participate in the maintenance of body temperature.

    “Brite adipocytes can express UCP1 and, as such, can participate in the maintenance of body temperature 90.”
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    • cites [90] Wu J, Cohen P, Spiegelman BM (2013) Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev 27: 234–250 source

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    Others have shown that the lack of FGF21 in long-term cold adaptation does not impair the thermogenic response of mice.

    “However, others have shown that the lack of FGF21 in long‐term cold adaptation does not impair the thermogenic response of mice 93.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Keipert S, Kutschke M, Ost M, Schwarzmayr T, van Schothorst EM, Lamp D, Brachthauser L, Hamp I, Mazibuko SE, Hartwig S et al (2017) Long‐term cold adaptation does not require FGF21 or UCP1. Cell Metab 26: 437–446 e5 source

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  • May combine two claims.

    Premisecitation

    Hepatic FGF21 production can also be induced by cold, and blunted hepatic FGF21 secretion, but not adipocytic FGF21 secretion, results in impaired cold tolerance and decreased sympathetic nerve activity in BAT.

    “Additionally, hepatic FGF21 production can also be induced by cold, and blunted hepatic FGF21 secretion, but not adipocytic FGF21 secretion, results in impaired cold tolerance and decreased sympathetic nerve activity in BAT 95.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Ameka M, Markan KR, Morgan DA, BonDurant LD, Idiga SO, Naber MC, Zhu Z, Zingman LV, Grobe JL, Rahmouni K et al (2019) Liver derived FGF21 maintains core body temperature during acute cold exposure. Sci Rep 9: 630 source

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  • May combine two claims.

    Premisecitation

    TGR5 adipose tissue-specific knockout mice show neglectable browning and exhibit reduced cold tolerance due to reduced adipose mitochondrial fusion.

    “These mice show neglectable browning and exhibit reduced cold tolerance due to reduced adipose mitochondrial fusion 98.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Velazquez‐Villegas LA, Perino A, Lemos V, Zietak M, Nomura M, Pols TWH, Schoonjans K (2018) TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue. Nat Commun 9: 245 source

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  • May combine two claims.

    Premisecitation

    BA secretion increases energy expenditure in BAT by enhancing the enzymatic activity of DIO2 and therefore regulating thyroid hormone metabolism in BAT.

    “It has been described that BA secretion increases energy expenditure in BAT by enhancing the enzymatic activity of DIO2 and therefore regulating thyroid hormone metabolism in BAT 97.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, Messaddeq N, Harney JW, Ezaki O, Kodama T et al (2006) Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439: 484–489 source

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  • May combine two claims.

    Premisecitation

    Activation of feeding-responsive thermogenesis is strongly associated with food intake regulation by inhibiting orexigenic activation in the brain, revealing a gut-brain-BAT-brain axis.

    “The activation of feeding–responsive thermogenesis has been strongly associated with food intake regulation by inhibiting orexigenic activation in the brain, revealing a gut–brain–BAT–brain axis 104.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Kelsey R (2018) BAT is involved in control of satiation. Nat Rev Endocrinol 15: 1 source

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  • May combine two claims.

    Premisereasoning

    Most periprandial gut hormones act through the brain, like GLP‐1 and CCK, where they increase sympathetic activation and stimulate local release of NE in BAT.

    “Most of these molecules act through the brain, like GLP‐1 and CCK, where they increase sympathetic activation and therefore stimulate the local release of NE in BAT.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Secretin can stimulate BAT thermogenesis in a non‐sympathetic manner and contribute to satiation.

    “Interestingly, secretin can stimulate BAT thermogenesis in a non‐sympathetic manner and contribute to satiation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Li Y, Schnabl K, Gabler SM, Willershauser M, Reber J, Karlas A, Laurila S, Lahesmaa M, U Din M, Bast‐Habersbrunner A et al (2018) Secretin‐activated brown fat mediates prandial thermogenesis to induce satiation. Cell 175: 1561–1574 e12 source

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  • May combine two claims.

    Premisecitation

    Secretin treatment increases the expression of anorexigenic POMC peptide in the hypothalamus and reduces food intake.

    “Moreover, secretin treatment increases the expression of the anorexigenic proopiomelanocortin (POMC) peptide in the hypothalamus and therefore reduces food intake 107.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Li Y, Schnabl K, Gabler SM, Willershauser M, Reber J, Karlas A, Laurila S, Lahesmaa M, U Din M, Bast‐Habersbrunner A et al (2018) Secretin‐activated brown fat mediates prandial thermogenesis to induce satiation. Cell 175: 1561–1574 e12 source

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  • May combine two claims.

    Interpretationreasoning

    Brown and beige adipose tissue thermogenesis are activated not only to adapt to cold stress but also to prevent excessive energy storage that could lead to obesity and thus maintain general energy homeostasis.

    “In this section, we described how brown and beige adipose tissue thermogenesis are activated not only to adapt to cold stress (Fig 3), but also to prevent the excessive energy storage that could lead to obesity and thus maintain general energy homeostasis in the organism.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Irisin can increase muscle oxidative metabolism and substrate uptake, and reduce hepatic glucose output.

    “Irisin can also increase muscle oxidative metabolism and substrate (glucose and fatty acid) uptake, and reduce hepatic glucose output 117.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Perakakis N, Triantafyllou GA, Fernandez‐Real JM, Huh JY, Park KH, Seufert J, Mantzoros CS (2017) Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol 13: 324–337 source

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  • May combine two claims.

    Premisecitation

    IL‐6 triggers insulin production in pancreas, hepatic glucose production, and adipose tissue lipolysis, thus ensuring the availability of energy substrates for exercising muscle.

    “IL‐6 also triggers insulin production in pancreas, hepatic glucose production, and adipose tissue lipolysis, thus ensuring the availability of energy substrates for exercising muscle 11, 17.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Giudice J, Taylor JM (2017) Muscle as a paracrine and endocrine organ. Curr Opin Pharmacol 34: 49–55 source

      Not checked in the free run.

    • cites [17] Pedersen BK, Febbraio MA (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8: 457–465 source

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  • May combine two claims.

    Premisecitation

    IL‐6 mediates muscle glucose uptake, increased insulin sensitivity, and increased fatty acid oxidation.

    “Exercise‐induced IL‐6 production was initially believed to be linked to muscle damage, but has now been proven to directly depend on contraction and to mediate muscle glucose uptake, increased insulin sensitivity, and increased fatty acid oxidation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Giudice J, Taylor JM (2017) Muscle as a paracrine and endocrine organ. Curr Opin Pharmacol 34: 49–55 source

      Not checked in the free run.

    • cites [17] Pedersen BK, Febbraio MA (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8: 457–465 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL‐6 induces an anti‐inflammatory response by reducing TNF‐α production while increasing the levels of IL‐10, IL‐1Ra, and IL‐15.

    “Moreover, IL‐6 has the ability to induce an anti‐inflammatory response by reducing tumor necrosis factor‐α (TNF‐α) production while increasing the levels of interleukin 10 (IL‐10), interleukin 1 receptor antagonist (IL‐1Ra), and interleukin 15 (IL‐15) 17, 114.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Pedersen BK, Febbraio MA (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8: 457–465 source

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    • cites [114] Leal LG, Lopes MA, Batista Jr ML (2018) Physical exercise‐induced myokines and muscle‐adipose tissue crosstalk: a review of current knowledge and the implications for health and metabolic diseases. Front Physiol 9: 1307 source

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  • May combine two claims.

    Premisecitation

    During exercise skeletal muscle tightly interacts with adipose tissue, pancreas, and liver to sustain the energy demands of physical activity and mediate positive effects in whole‐body energy metabolism.

    “More precisely, during exercise skeletal muscle tightly interacts with adipose tissue, pancreas, and liver to sustain the energy demands of physical activity and mediate positive effects in whole‐body energy metabolism.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Giudice J, Taylor JM (2017) Muscle as a paracrine and endocrine organ. Curr Opin Pharmacol 34: 49–55 source

      Not checked in the free run.

    • cites [17] Pedersen BK, Febbraio MA (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8: 457–465 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obese humans and DIO mice do not show the expected reduction in food intake and increase in energy expenditure, leading to the concept of leptin resistance, probably due to a decrease in JAK2‐STAT3 signaling in pathologic conditions.

    “Despite this, they do not show the expected reduction in food intake and increase in energy expenditure, thus leading to the concept of leptin resistance, probably due to a decrease in JAK2‐STAT3 signaling in pathologic conditions 127.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] Munzberg H, Flier JS, Bjorbaek C (2004) Region‐specific leptin resistance within the hypothalamus of diet‐induced obese mice. Endocrinology 145: 4880–4889 source

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  • May combine two claims.

    Premisecitation

    Cold‐induced muscle shivering can increase circulating irisin levels and promote brown fat thermogenesis.

    “Interestingly, cold‐induced muscle shivering can increase circulating irisin levels and promote brown fat thermogenesis 118 (Fig 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C, Perron RM, Werner CD, Phan GQ, Kammula US et al (2014) Irisin and FGF21 are cold‐induced endocrine activators of brown fat function in humans. Cell Metab 19: 302–309 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The secreted form of lysosomal enzyme cathepsin B (CTSB) is an exercise‐responsive myokine that targets the brain, promotes hippocampal neurogenesis, and therefore enhances cognitive abilities.

    “Finally, a recent study using proteomic approaches demonstrates that the secreted form of lysosomal enzyme cathepsin B (CTSB) is also an exercise–responsive myokine that targets the brain, promotes hippocampal neurogenesis, and therefore enhances cognitive abilities 122.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Moon HY, Becke A, Berron D, Becker B, Sah N, Benoni G, Janke E, Lubejko ST, Greig NH, Mattison JA et al (2016) Running‐induced systemic cathepsin B secretion is associated with memory function. Cell Metab 24: 332–340 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most humans with obesity, as well as DIO mice fed highly caloric palatable diets, develop insulin resistance and exhibit high plasma levels of leptin.

    “Most humans with obesity, as well as DIO mice, fed highly caloric palatable diets, develop insulin resistance, and exhibit high plasma levels of leptin 35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS (1995) Leptin levels reflect body lipid content in mice: evidence for diet‐induced resistance to leptin action. Nat Med 1: 1311–1314 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Physical exercise promotes the browning of WAT and BAT thermogenesis, possibly to meet the increased demand for fatty acid and glucose oxidation and to prevent the accumulation of energy substrates in the circulation.

    “Moreover, physical exercise also promotes the browning of WAT and BAT thermogenesis, possibly in order to meet the increased demand for fatty acid and glucose oxidation and to prevent the accumulation of energy substrates in the circulation 123, 124.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [123] Virtanen KA (2014) BAT thermogenesis: linking shivering to exercise. Cell Metab 19: 352–354 source

      Not checked in the free run.

    • cites [124] Aldiss P, Betts J, Sale C, Pope M, Budge H, Symonds ME (2018) Exercise‐induced ‘browning’ of adipose tissues. Metabolism 81: 63–70 source

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  • May combine two claims.

    Premisecitation

    Increased NPY expression triggers a reduction in the expression of tyrosine hydroxylase neurons in the PVN of the hypothalamus and consequently diminishes the thermogenic activation of BAT and overall energy expenditure.

    “This increase triggers a reduction in the expression of tyrosine hydroxylase neurons in the paraventricular nucleus (PVN) of the hypothalamus and consequently, diminishes the thermogenic activation of BAT and overall energy expenditure 129.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Shi YC, Lau J, Lin Z, Zhang H, Zhai L, Sperk G, Heilbronn R, Mietzsch M, Weger S, Huang XF et al (2013) Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab 17: 236–248 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clinical studies in humans have revealed high FGF21 circulating concentrations in obese and insulin‐resistant subjects, as well as the onset of FGF21 resistance.

    “Moreover, despite evidence showing improved metabolic fitness in FGF21 treatment or overexpression studies, clinical studies in humans have revealed high FGF21 circulating concentrations in obese and insulin‐resistant subjects, as well as the onset of a so called “FGF21 resistance” 134.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS, Maratos‐Flier E (2010) Obesity is a fibroblast growth factor 21 (FGF21)‐resistant state. Diabetes 59: 2781–2789 source

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  • May combine two claims.

    Premisecitation

    Activation of adiponectin signaling has improved glucose tolerance, insulin sensitivity, and longevity in mice.

    “So far, the activation of adiponectin signaling has improved glucose tolerance, insulin sensitivity, and longevity in mice 12, 130.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Fasshauer M, Bluher M (2015) Adipokines in health and disease. Trends Pharmacol Sci 36: 461–470 source

      Not checked in the free run.

    • cites [130] Okada‐Iwabu M, Yamauchi T, Iwabu M, Honma T, Hamagami K, Matsuda K, Yamaguchi M, Tanabe H, Kimura‐Someya T, Shirouzu M et al (2013) A small‐molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 503: 493–499 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Postprandial GLP‐1 secretion is increased in obese patients following bariatric surgery and correlates with weight loss maintenance.

    “Interestingly, postprandial glucagon‐like peptide‐1 (GLP‐1) secretion is increased in obese patients following bariatric surgery and correlates with weight loss maintenance 139.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Madsbad S (2014) The role of glucagon‐like peptide‐1 impairment in obesity and potential therapeutic implications. Diabetes Obes Metab 16: 9–21 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Improving muscle oxidative capacity is beneficial both to prevent metabolic disease and to cure metabolic disease.

    “These findings highlight the fact that improving muscle oxidative capacity is beneficial both to prevent metabolic disease and to cure metabolic disease; however, the role of Lcn5 and Metrnl in normal physiology remains to be determined.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Physical inactivity is associated with decreased insulin sensitivity, reduced postprandial lipid metabolism, decreased muscle mass, and obesity.

    “Physical inactivity, that can be both a cause and a consequence of obesity, is known to be associated with decreased insulin sensitivity, reduced postprandial lipid metabolism, decreased muscle mass, and obesity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Hoffmann C, Weigert C (2017) Skeletal muscle as an endocrine organ: the role of myokines in exercise adaptations. Cold Spring Harb Perspect Med 7: a029793 source

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  • May combine two claims.

    Premisecitation

    Serum Metrnl levels are decreased in patients with T2D and inversely correlate with fasting glucose levels.

    “However, serum Metrnl levels are decreased in patients with T2D and inversely correlate with fasting glucose levels 137.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Lee JH, Kang YE, Kim JM, Choung S, Joung KH, Kim HJ, Ku BJ (2018) Serum Meteorin‐like protein levels decreased in patients newly diagnosed with type 2 diabetes. Diabetes Res Clin Pract 135: 7–10 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metrnl promotes adipose tissue browning by recruiting IL‐4 and IL‐13 producing eosinophils and thus promoting anti‐inflammatory macrophage activation.

    “Metrnl promotes adipose tissue browning by recruiting IL‐4 and IL‐13 producing eosinophils and thus promoting anti‐inflammatory macrophage activation 136.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136] Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar I, Jedrychowski MP, Ruas JL, Wrann CD, Lo JC et al (2014) Meteorin‐like is a hormone that regulates immune‐adipose interactions to increase beige fat thermogenesis. Cell 157: 1279–1291 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The use of leptin analogs in combination with amylin gave more encouraging results but was stopped due to adverse secondary effects.

    “However, the use of leptin analogs in combination with other agents, namely amylin, has given more encouraging results, but was stopped due to adverse secondary effects 12.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Fasshauer M, Bluher M (2015) Adipokines in health and disease. Trends Pharmacol Sci 36: 461–470 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice deficient for myostatin show an improved metabolic phenotype and a resistance to HFD.

    “Importantly, the inhibition of myostatin signaling increases PGC1α and mitochondrial biogenesis 145, while mice deficient for myostatin show an improved metabolic phenotype and a resistance to HFD 146, 147.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [146] Zhao B, Wall RJ, Yang J (2005) Transgenic expression of myostatin propeptide prevents diet‐induced obesity and insulin resistance. Biochem Biophys Res Commun 337: 248–255 source

      Not checked in the free run.

    • cites [147] Shan T, Liang X, Bi P, Kuang S (2013) Myostatin knockout drives browning of white adipose tissue through activating the AMPK‐PGC1alpha‐Fndc5 pathway in muscle. FASEB J 27: 1981–1989 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adiponectin receptor analogs have successfully been used in preclinical mouse models but have not yet been used in human patients.

    “Adiponectin receptor analogs have successfully been used in preclinical mouse models 130, but have not yet been used in human patients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Okada‐Iwabu M, Yamauchi T, Iwabu M, Honma T, Hamagami K, Matsuda K, Yamaguchi M, Tanabe H, Kimura‐Someya T, Shirouzu M et al (2013) A small‐molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 503: 493–499 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A truncated globular form of adiponectin promotes muscle fatty acid oxidation, decreases muscle ceramides, and overall improves insulin sensitivity.

    “A truncated globular form of adiponectin has also been shown to promote muscle fatty acid oxidation, decrease muscle ceramides, and overall improve insulin sensitivity, whether or not this globular adiponectin mimics the function of the multimeric adiponectin complexes found in circulation remains to be demonstrated 39.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Stern JH, Rutkowski JM, Scherer PE (2016) Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab 23: 770–784 source

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  • May combine two claims.

    Premisecitation

    GLP‐1Ras improve glycemic control and reduce liver inflammation and fibrosis.

    “Moreover, GLP‐1Ras improve glycemic control and reduce liver inflammation and fibrosis 157.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [157] Andersen A, Lund A, Knop FK, Vilsboll T (2018) Glucagon‐like peptide 1 in health and disease. Nat Rev Endocrinol 14: 390–403 source

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  • May combine two claims.

    Premisecitation

    More than 15% of the protein‐coding genome encodes for roughly 3,000 secreted proteins, but only a handful of them has been properly annotated.

    “Recent studies show that more than 15% of the protein‐coding genome encodes for roughly 3,000 secreted proteins, but only a handful of them has been properly annotated 159, 160, suggesting that a very high number of “molecular messengers” remain to be discovered.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [159] Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, Zwahlen M, Kampf C, Wester K, Hober S et al (2010) Towards a knowledge‐based Human Protein Atlas. Nat Biotechnol 28: 1248–1250 source

      Not checked in the free run.

    • cites [160] Lindskog C (2015) The potential clinical impact of the tissue‐based map of the human proteome. Expert Rev Proteomics 12: 213–215 source

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  • May combine two claims.

    Premisecitation

    A neutralizing antibody against asprosin reduces appetite, body weight, and blood glucose in obese mice.

    “More recently, a neutralizing antibody against asprosin was used in obese mice to reduce appetite, body weight, and blood glucose, suggesting that this orexigenic hormone can be targeted to modulate food intake and lower glycemia in obese subjects 60.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Duerrschmid C, He Y, Wang C, Li C, Bournat JC, Romere C, Saha PK, Lee ME, Phillips KJ, Jain M et al (2017) Asprosin is a centrally acting orexigenic hormone. Nat Med 23: 1444–1453 source

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  • May combine two claims.

    Premisecitation

    Recombinant FGF21 or FGF21 variants have beneficial metabolic effects in mice; only a small trend toward glucose lowering was reported in humans.

    “Extensive efforts have also been made with the use of recombinant FGF21 or FGF21 variants as potential therapy, due to beneficial metabolic effects observed in mice 152, 153; however, only a small trend toward glucose lowering was reported in humans 154.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [152] Zhang C, Huang Z, Gu J, Yan X, Lu X, Zhou S, Wang S, Shao M, Zhang F, Cheng P et al (2015) Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal‐regulated kinase 1/2‐dependent signalling pathway. Diabetologia 58: 1937–1948 source

      Not checked in the free run.

    • cites [153] Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, Vonderfecht S, Hecht R, Li YS, Lindberg RA et al (2009) Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet‐induced obese mice. Diabetes 58: 250–259 source

      Not checked in the free run.

    • cites [154] Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, Kharitonenkov A, Bumol T, Schilske HK, Moller DE (2013) The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab 18: 333–340 source

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  • The quote only partly states this claim.

    Interpretationcitation

    Asprosin can be targeted to modulate food intake and lower glycemia in obese subjects.

    “More recently, a neutralizing antibody against asprosin was used in obese mice to reduce appetite, body weight, and blood glucose, suggesting that this orexigenic hormone can be targeted to modulate food intake and lower glycemia in obese subjects 60.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Duerrschmid C, He Y, Wang C, Li C, Bournat JC, Romere C, Saha PK, Lee ME, Phillips KJ, Jain M et al (2017) Asprosin is a centrally acting orexigenic hormone. Nat Med 23: 1444–1453 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GLP‐1 receptor agonists trigger a reduction in body weight by promoting satiety and reducing food intake, and have a longer half‐life than endogenous GLP‐1.

    “Significant preclinical and clinical success, however, has been encountered by using GLP‐1 receptor agonists (GLP‐1Ras), that trigger a reduction in body weight by promoting satiety and reducing food intake, and profit from a longer half‐life than endogenous GLP‐1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [157] Andersen A, Lund A, Knop FK, Vilsboll T (2018) Glucagon‐like peptide 1 in health and disease. Nat Rev Endocrinol 14: 390–403 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adipose tissue exosomes carrying circulating miRNAs have far‐reaching effects in other peripheral tissues and can be considered the most recent family of adipokines.

    “More precisely, adipose tissue exosomes carrying circulating miRNAs have recently been shown to have far‐reaching effects in other peripheral tissues, and can therefore be considered the most recent family of adipokines 171.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171] Thomou T, Mori MA, Dreyfuss JM, Konishi M, Sakaguchi M, Wolfrum C, Rao TN, Winnay JN, Garcia‐Martin R, Grinspoon SK et al (2017) Adipose‐derived circulating miRNAs regulate gene expression in other tissues. Nature 542: 450–455 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The findings summarized in this review highlight the importance of inter‐organ communication in health and disease.

    “Overall, the findings summarized in this review highlight the importance of inter‐organ communication in health and disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Upon cold exposure, WAT produces free fatty acids that promote hepatic acylcarnitine production; these acylcarnitines are used by BAT for adaptive thermogenesis.

    “In one instance, Simcox and colleagues showed that upon cold exposure, WAT produces free fatty acids that, in turn, promote hepatic acylcarnitine production. These acylcarnitines are in fine used by BAT for adaptive thermogenesis 163.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Simcox J, Geoghegan G, Maschek JA, Bensard CL, Pasquali M, Miao R, Lee S, Jiang L, Huck I, Kershaw EE et al (2017) Global analysis of plasma lipids identifies liver‐derived acylcarnitines as a fuel source for brown fat thermogenesis. Cell Metab 26: 509–522 e6 source

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  • May combine two claims.

    Premisecitation

    Comparing RNA sequencing of jejunum and stomach between sham and gastric sleeve bypass allowed the identification of LEAP2, an endogenous antagonist of the ghrelin receptor, which may contribute to the efficiency of gastric bypass.

    “Comparing RNA sequencing of jejunum and stomach when comparing sham and gastric sleeve bypass allowed the identification of LEAP2, an endogenous antagonist of the ghrelin receptor, which may contribute to the efficiency of gastric bypass 47.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Ge X, Yang H, Bednarek MA, Galon‐Tilleman H, Chen P, Chen M, Lichtman JS, Wang Y, Dalmas O, Yin Y et al (2018) LEAP2 is an endogenous antagonist of the ghrelin receptor. Cell Metab 27: 461–469 e6 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The direct use of specific diets, or the modulation of inter‐organ communication, could have a pharmacological effect on its own or increase the efficiency of pharmacological approaches.

    “Therefore, the direct use of specific diets, or the modulation of inter‐organ communication, could have a pharmacological effect on its own 167 or increase the efficiency of pharmacological approaches to treat a wide variety of diseases 173, 174.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [167] Trompette A, Gollwitzer ES, Pattaroni C, Lopez‐Mejia IC, Riva E, Pernot J, Ubags N, Fajas L, Nicod LP, Marsland BJ (2018) Dietary fiber confers protection against flu by shaping Ly6c(−) patrolling monocyte hematopoiesis and CD8(+) T cell metabolism. Immunity 48: 992–1005 e8 source

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    • cites [173] Hopkins BD, Pauli C, Du X, Wang DG, Li X, Wu D, Amadiume SC, Goncalves MD, Hodakoski C, Lundquist MR et al (2018) Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560: 499–503 source

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    • cites [174] Quail DF, Olson OC, Bhardwaj P, Walsh LA, Akkari L, Quick ML, Chen IC, Wendel N, Ben‐Chetrit N, Walker J et al (2017) Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM‐CSF. Nat Cell Biol 19: 974–987 source

      Not checked in the free run.

69 of 69

  • The paper relies on this without support.

    Multidirectional interactions between peripheral metabolic organs and the central nervous system maintain whole-body energy homeostasis and ensure adaptation to external cues.

    “Multidirectional interactions between metabolic organs in the periphery and the central nervous system have evolved concomitantly with multicellular organisms to maintain whole‐body energy homeostasis and ensure the organism's adaptation to external cues.”

  • The paper relies on this without support.

    These interactions are altered in pathological conditions such as obesity and type 2 diabetes.

    “These interactions are altered in pathological conditions such as obesity and type 2 diabetes.”

  • The paper relies on this without support.

    Bioactive peptides and proteins, such as hormones and cytokines, produced by both peripheral organs and the central nervous system, are key messengers in inter-organ communication.

    “Bioactive peptides and proteins, such as hormones and cytokines, produced by both peripheral organs and the central nervous system, are key messengers in this inter‐organ communication.”

  • The paper relies on this without support.

    Inter-organ communication is altered in different pathologic conditions, for example, in conditions related to adipose tissue dysfunction, like obesity.

    “Inter‐organ communication is altered in different pathologic conditions, for example, in conditions related to adipose tissue dysfunction, like obesity.”

  • The paper relies on this without support.

    Alterations in hormones and cytokines contribute to the spectrum of obesity-associated pathologies.

    “As such, alterations in hormones and cytokines are currently known to notably contribute to the spectrum of obesity‐associated pathologies.”

  • The paper relies on this without support.

    Pharmacological interventions to modify the production of hormones/cytokines, or directly delivering recombinant hormones/cytokines, are promising approaches to treat obesity-related endocrine diseases.

    “Therefore, pharmacological interventions to modify the production of hormones/cytokines, or directly delivering recombinant hormones/cytokines, are currently being explored as promising approaches to treat a wide variety of obesity‐related endocrine diseases.”
6 of 6

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.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Myostatin deficiency has opposite reported effects on insulin resistance

    Minor

    The text says myostatin-deficient mice develop insulin resistance, but the title of its cited reference 148 says they exhibit reduced insulin resistance. This reverses the reported metabolic effect.

1 of 1

Cites

Flagged first, then by citations

2 of the 177 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Bernard C (1853) Nouvelle fonction du foie considéré comme organe producteur de matière sucrée chez l'homme et les animaux. Paris: Baillère JB

Cited by

Sorted by citations

Related

Authors
Castillo‐Armengol, J., Fajas, L., & Lopez‐Mejia, I. C.
Affiliations
University of Lausanne (CH)
ORCID
Venue
The EMBO Reports
Publisher
Springer Science and Business Media LLC
Published
2019-08-19
Volume
20
Issue
9
Pages
e47903-e47903
ISSN
  • 1469-221X (ISSN-L)
  • 1469-3178
DOI
10.15252/embr.201947903
PMC
PMC6726901
OpenAlex
W2969433956
Cited by
178
References
177
Citations by year
2026: 24 · 2025: 29 · 2024: 35 · 2023: 28 · 2022: 29 · 2021: 19 · 2020: 13 · 2019: 1
FWCI
1.86
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Reports (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • SERVAL (Université de Lausanne) (publishedVersion, cc-by)
  • IRIS (submittedVersion, cc-by)
Funders
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (168077)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords
inter-organ communication, gut-brain axis, energy homeostasis, metabolic crosstalk, hormones, cytokines, bioactive peptides, obesity, type 2 diabetes, metabolic disorders, treatment options
MeSH terms
Animals, Diabetes Mellitus, Type 2, Energy Metabolism, Homeostasis, Humans, Models, Biological, Obesity

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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.

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