Inter‐organ communication: a gatekeeper for metabolic health

In the paper

“Peripheral organs and immune cells can also produce smaller bioactive proteins, namely cytokines 1, that also participate in inter‐organ communication.”

What the sources say

• Not checked yetcites [1] Dinarello CA (2007) Historical insights into cytokines. Eur J Immunol 37(Suppl 1): S34–S45 source

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [23] Chu JY, Cheng CY, Sekar R, Chow BK (2013) Vagal afferent mediates the anorectic effect of peripheral secretin. PLoS One 8: e64859 source

In the paper

“A major target for gut‐derived hormones is the vagal afferent neurons (VANs) 21.”

What the sources say

• Not checked yetcites [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

In the paper

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

What the sources say

• Not checked yetcites [24] Tokarz VL, MacDonald PE, Klip A (2018) The cell biology of systemic insulin function. J Cell Biol 217: 2273–2289 source

In the paper

“GLP‐1 and GIP work synergistically to potentiate glucose‐stimulated insulin secretion by pancreatic β‐cells 21.”

What the sources say

• Not checked yetcites [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

In the paper

“The secretion of these signaling molecules varies according to the metabolic status of the body. They respond for instance to fasting and feeding cycles 14, to the circadian rhythm 15, to cold exposure 16, and to exercise17, thus participating in the organism's adaptive response and ensuring metabolic flexibility.”

What the sources say

• Not checked yetcites [14] Longo VD, Panda S (2016) Fasting, circadian rhythms, and time‐restricted feeding in healthy lifespan. Cell Metab 23: 1048–1059 source
• Not checked yetcites [15] Gnocchi D, Bruscalupi G (2017) Circadian rhythms and hormonal homeostasis: pathophysiological implications. Biology (Basel) 6: 10
• Not checked yetcites [16] Betz MJ, Enerback S (2015) Human brown adipose tissue: what we have learned so far. Diabetes 64: 2352–2360 source

In the paper

“In parallel, glucose inhibits the release of glucagon from the pancreatic α‐cells 25, 26.”

What the sources say

• Not checked yetcites [25] Kersten S (2001) Mechanisms of nutritional and hormonal regulation of lipogenesis. EMBO Rep 2: 282–286 source
• Not checked yetcites [26] Vieira E, Salehi A, Gylfe E (2007) Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells. Diabetologia 50: 370–379 source

In the paper

“Leptin is secreted by white adipocytes proportionally to TG stores 35, 36, 37.”

What the sources say

• Not checked yetcites [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 yetcites [36] Ingalls AM, Dickie MM, Snell GD (1950) Obese, a new mutation in the house mouse. J Hered 41: 317–318 source
• Not checked yetcites [37] Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425–432 source

In the paper

“Importantly, LEAP2 was reported to be an endogenous antagonist of the ghrelin receptor, or growth hormone secretagogue receptor (GHSR).”

What the sources say

• Not checked yetcites [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

In the paper

“The effects of ghrelin on adiposity have been shown to require intact sympathetic nervous system signaling 53.”

What the sources say

• Not checked yetcites [53] Theander‐Carrillo C, Wiedmer P, Cettour‐Rose P, Nogueiras R, Perez‐Tilve D, Pfluger P, Castaneda TR, Muzzin P, Schurmann A, Szanto I et al (2006) Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest 116: 1983–1993 source

In the paper

“This reduction in leptin promotes a switch between the “fasted state” and the “fed state” by promoting food intake and reducing energy expenditure 54.”

What the sources say

• Not checked yetcites [54] Jackson MB, Ahima RS (2006) Neuroendocrine and metabolic effects of adipocyte‐derived hormones. Clin Sci (Lond) 110: 143–152 source

In the paper

“Ghrelin attenuates insulin production and increases blood glucose concentration by promoting the intracellular localization of the pancreatic β‐cell GLP‐1R under fasting conditions, thus counteracting GLP‐1 signaling 21.”

What the sources say

• Not checked yetcites [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

In the paper

“Ghrelin also stimulates glucagon secretion in pancreatic α‐cells 51.”

What the sources say

• Not checked yetcites [51] Chuang JC, Sakata I, Kohno D, Perello M, Osborne‐Lawrence S, Repa JJ, Zigman JM (2011) Ghrelin directly stimulates glucagon secretion from pancreatic alpha‐cells. Mol Endocrinol 25: 1600–1611 source

In the paper

“In contrast to leptin, adiponectin levels increase in low glucose and low insulin conditions, at least in the cerebrospinal fluid (CSF) 55, 56.”

What the sources say

• Not checked yetcites [55] Steinberg GR, Kemp BE (2007) Adiponectin: starving for attention. Cell Metab 6: 3–4 source
• Not checked yetcites [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

In the paper

“Moreover, ghrelin can directly promote adiposity, independently of food intake or GH secretion, by increasing carbohydrate use, stimulating lipid synthesis, and reducing fatty acid oxidation 50, 52.”

What the sources say

• Not checked yetcites [50] Al Massadi O, Lopez M, Tschop M, Dieguez C, Nogueiras R (2017) Current understanding of the hypothalamic ghrelin pathways inducing appetite and adiposity. Trends Neurosci 40: 167–180 source
• Not checked yetcites [52] Tschop M, Smiley DL, Heiman ML (2000) Ghrelin induces adiposity in rodents. Nature 407: 908–913 source

In the paper

“Asprosin, a novel fasting‐induced adipokine that promotes hepatic glucose production, was recently identified 59.”

What the sources say

• Not checked yetcites [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

In the paper

“Additionally, asprosin can directly target the central nervous system (CNS) to increase food intake 60.”

What the sources say

• Not checked yetcites [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

In the paper

“Hypothalamic expression of bone morphogenetic protein 8b (BMP8b) in the VMH stimulates orexin secretion in the LHA through a decrease in AMPK activity and thus enhances the firing of projections that will stimulate BAT thermogenesis 79.”

What the sources say

• Not checked yetcites [79] Martins L, Seoane‐Collazo P, Contreras C, Gonzalez‐Garcia I, Martinez‐Sanchez N, Gonzalez F, Zalvide J, Gallego R, Dieguez C, Nogueiras R et al (2016) A functional link between AMPK and orexin mediates the effect of BMP8B on energy balance. Cell Rep 16: 2231–2242 source

In the paper

“Therefore, cell‐to‐cell communication via connexin 43 (CX43) containing gap junctions is essential to disseminating adrenergic activation signals 72.”

What the sources say

• Not checked yetcites [72] Zhu Y, Gao Y, Tao C, Shao M, Zhao S, Huang W, Yao T, Johnson JA, Liu T, Cypess AM et al (2016) Connexin 43 mediates white adipose tissue beiging by facilitating the propagation of sympathetic neuronal signals. Cell Metab 24: 420–433 source

In the paper

“Moreover, orexin infusion into the VMH can stimulate the sympathetic firing in BAT 78.”

What the sources say

• Not checked yetcites [78] Monda M, Viggiano AN, Viggiano A, Viggiano E, Lanza A, De Luca V (2005) Hyperthermic reactions induced by orexin A: role of the ventromedial hypothalamus. Eur J Neurosci 22: 1169–1175 source

In the paper

“Hypoglycemia is directly sensed by GLUT2‐positive hypothalamic neurons that promote glucagon secretion via an increase in parasympathetic input 66.”

What the sources say

• Not checked yetcites [66] Lamy CM, Sanno H, Labouebe G, Picard A, Magnan C, Chatton JY, Thorens B (2014) Hypoglycemia‐activated GLUT2 neurons of the nucleus tractus solitarius stimulate vagal activity and glucagon secretion. Cell Metab 19: 527–538 source

In the paper

“Notably, direct innervation of WAT depots is sparser than in BAT 69.”

What the sources say

• Not checked yetcites [69] Zeng W, Pirzgalska RM, Pereira MM, Kubasova N, Barateiro A, Seixas E, Lu YH, Kozlova A, Voss H, Martins GG et al (2015) Sympathetic neuro‐adipose connections mediate leptin‐driven lipolysis. Cell 163: 84–94 source

In the paper

“This increased SNS tone in WAT could be directly triggered by hypoglycemia sensing in the brain 67, 68.”

What the sources say

• Not checked yetcites [67] Garretson JT, Szymanski LA, Schwartz GJ, Xue B, Ryu V, Bartness TJ (2016) Lipolysis sensation by white fat afferent nerves triggers brown fat thermogenesis. Mol Metab 5: 626–634 source
• Not checked yetcites [68] Geerling JJ, Boon MR, Kooijman S, Parlevliet ET, Havekes LM, Romijn JA, Meurs IM, Rensen PC (2014) Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies. J Lipid Res 55: 180–189 source

In the paper

“This process is characterized by the appearance of brite (from brown‐in‐white) adipocytes, also called beige adipocytes, mainly in subcutaneous WAT.”

What the sources say

• Not checked yetcites [90] Wu J, Cohen P, Spiegelman BM (2013) Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev 27: 234–250 source

In the paper

“Similarly, administration of the incretin hormone GLP‐1 in the DMH increases BAT thermogenesis 82.”

What the sources say

• Not checked yetcites [82] Lee SJ, Sanchez‐Watts G, Krieger JP, Pignalosa A, Norell PN, Cortella A, Pettersen KG, Vrdoljak D, Hayes MR, Kanoski SE et al (2018) Loss of dorsomedial hypothalamic GLP‐1 signaling reduces BAT thermogenesis and increases adiposity. Mol Metab 11: 33–46 source

In the paper

“Apart from catecholamines, thyroid hormones can also trigger BAT activity 86.”

What the sources say

• Not checked yetcites [86] Obregon MJ (2014) Adipose tissues and thyroid hormones. Front Physiol 5: 479 source

In the paper

“These nerves express tyrosine hydroxylase, the enzyme responsible for the secretion of the catecholamine hormone NE 84.”

What the sources say

• Not checked yetcites [84] Bartness TJ, Vaughan CH, Song CK (2010) Sympathetic and sensory innervation of brown adipose tissue. Int J Obes (Lond) 34(Suppl 1): S36–S42 source

In the paper

“It has been broadly discussed that sympathetic nerves are present within the parenchyma of adipose tissue 83.”

What the sources say

• Not checked yetcites [83] Murano I, Barbatelli G, Giordano A, Cinti S (2009) Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ. J Anat 214: 171–178 source

In the paper

“For example, a chemical stimulation of this area increases the thermogenic response in rats 81.”

What the sources say

• Not checked yetcites [81] Zaretskaia MV, Zaretsky DV, Shekhar A, DiMicco JA (2002) Chemical stimulation of the dorsomedial hypothalamus evokes non‐shivering thermogenesis in anesthetized rats. Brain Res 928: 113–125 source

In the paper

“The relevance of thyroid hormone regulation for BAT function is illustrated by the blunted thermogenic response observed in DIO2 knockout mice, despite their increased UCP1 expression 89.”

What the sources say

• Not checked yetcites [89] Christoffolete MA, Linardi CC, de Jesus L, Ebina KN, Carvalho SD, Ribeiro MO, Rabelo R, Curcio C, Martins L, Kimura ET et al (2004) Mice with targeted disruption of the Dio2 gene have cold‐induced overexpression of the uncoupling protein 1 gene but fail to increase brown adipose tissue lipogenesis and adaptive thermogenesis. Diabetes 53: 577–584 source

In the paper

“The thyroid hormones T3 and T4 are synthetized in the thyroid gland upon hypothalamic stimulation of the pituitary gland and thyroid‐stimulating hormone (TSH) production 87.”

What the sources say

• Not checked yetcites [87] Brent GA (2012) Mechanisms of thyroid hormone action. J Clin Invest 122: 3035–3043 source

In the paper

“In brown adipocytes, T4 can be converted to its active form T3 via type 2 iodothyronine deiodinase (DIO2) thus compensating for the low levels of thyroid gland‐secreted T3 88.”

What the sources say

• Not checked yetcites [88] Bianco AC, McAninch EA (2013) The role of thyroid hormone and brown adipose tissue in energy homoeostasis. Lancet Diabetes Endocrinol 1: 250–258 source

In the paper

“Peptidase M20 domain‐containing 1 (PM20D1), a secreted enzyme produced by brown and brite adipocytes, has been recently discovered to contribute to this alternative thermogenesis by participating in the uncoupling of mitochondria in an UCP1‐independent manner 99, 100.”

What the sources say

• Not checked yetcites [99] Long JZ, Roche AM, Berdan CA, Louie SM, Roberts AJ, Svensson KJ, Dou FY, Bateman LA, Mina AI, Deng Z et al (2018) Ablation of PM20D1 reveals N‐acyl amino acid control of metabolism and nociception. Proc Natl Acad Sci USA 115: E6937–E6945
• Not checked yetcites [100] Long JZ, Svensson KJ, Bateman LA, Lin H, Kamenecka T, Lokurkar IA, Lou J, Rao RR, Chang MR, Jedrychowski MP et al (2016) The secreted enzyme PM20D1 regulates lipidated amino acid uncouplers of mitochondria. Cell 166: 424–435 source

In the paper

“However, recent research demonstrates that UCP1 is not essential for non‐shivering thermogenesis 93, 99, 100.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [99] Long JZ, Roche AM, Berdan CA, Louie SM, Roberts AJ, Svensson KJ, Dou FY, Bateman LA, Mina AI, Deng Z et al (2018) Ablation of PM20D1 reveals N‐acyl amino acid control of metabolism and nociception. Proc Natl Acad Sci USA 115: E6937–E6945
• Not checked yetcites [100] Long JZ, Svensson KJ, Bateman LA, Lin H, Kamenecka T, Lokurkar IA, Lou J, Rao RR, Chang MR, Jedrychowski MP et al (2016) The secreted enzyme PM20D1 regulates lipidated amino acid uncouplers of mitochondria. Cell 166: 424–435 source

In the paper

“Moreover, studies using BA receptor TGR5 adipose tissue‐specific knockout mice proved that BAs also participate in the browning of WAT.”

What the sources say

• Not checked yetcites [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

In the paper

“Besides their role in the digestion of dietary lipids, hepatic BAs can be induced by cold exposure 96.”

What the sources say

• Not checked yetcites [96] Worthmann A, John C, Ruhlemann MC, Baguhl M, Heinsen FA, Schaltenberg N, Heine M, Schlein C, Evangelakos I, Mineo C et al (2017) Cold‐induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis. Nat Med 23: 839–849 source

In the paper

“Despite the evidence of FGF21 production in WAT, controversial results were published by Véniant et al 94 who demonstrated that beneficial effects of weight loss observed after cold were not directly related to FGF21‐induced browning.”

What the sources say

• Not checked yetcites [94] Veniant MM, Sivits G, Helmering J, Komorowski R, Lee J, Fan W, Moyer C, Lloyd DJ (2015) Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. Cell Metab 21: 731–738 source

In the paper

“Indeed, physical exercise is not only beneficial because of the immediate increase in energy expenditure; it also remodels whole‐body energy metabolism.”

What the sources say

• Not checked yetcites [11] Giudice J, Taylor JM (2017) Muscle as a paracrine and endocrine organ. Curr Opin Pharmacol 34: 49–55 source

In the paper

“The actions of leptin and insulin in POMC neurons can also be triggered by a decrease in the hypothalamic levels of T‐cell protein tyrosine phosphatase (TCPTP), which is a negative regulator of insulin signaling, to further increase the browning of WAT and energy expenditure 108, 109.”

What the sources say

• Not checked yetcites [108] Dodd GT, Decherf S, Loh K, Simonds SE, Wiede F, Balland E, Merry TL, Munzberg H, Zhang ZY, Kahn BB et al (2015) Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160: 88–104 source
• Not checked yetcites [109] Dodd GT, Andrews ZB, Simonds SE, Michael NJ, DeVeer M, Bruning JC, Spanswick D, Cowley MA, Tiganis T (2017) A hypothalamic phosphatase switch coordinates energy expenditure with feeding. Cell Metab 26: 375–393 e7 source

In the paper

“In particular, feeding activates the secretion of periprandial gut hormones, such as CCK, GLP‐1, or secretin 105, 106, 107.”

What the sources say

• Not checked yetcites [105] Beiroa D, Imbernon M, Gallego R, Senra A, Herranz D, Villarroya F, Serrano M, Ferno J, Salvador J, Escalada J et al (2014) GLP‐1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 63: 3346–3358 source
• Not checked yetcites [106] Blouet C, Schwartz GJ (2012) Duodenal lipid sensing activates vagal afferents to regulate non‐shivering brown fat thermogenesis in rats. PLoS One 7: e51898 source
• Not checked yetcites [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

In the paper

“This mechanism can limit the effects of diet‐induced obesity (DIO).”

In the paper

“It has been demonstrated by several groups that there is a meal‐associated thermogenesis 101, 102, 103.”

What the sources say

• Not checked yetcites [101] Glick Z (1982) Inverse relationship between brown fat thermogenesis and meal size: the thermostatic control of food intake revisited. Physiol Behav 29: 1137–1140 source
• Not checked yetcites [102] Ud M, Saari T, Raiko J, Kudomi N, Maurer SF, Lahesmaa M, Fromme T, Amri EZ, Klingenspor M, Solin O et al (2018) Postprandial oxidative metabolism of human brown fat indicates thermogenesis. Cell Metab 28: 207–216 e3 source
• Not checked yetcites [103] Saito M (2013) Brown adipose tissue as a regulator of energy expenditure and body fat in humans. Diabetes Metab J 37: 22–29 source

In the paper

“A secretin injection in fasted mice directly activates BAT thermogenesis by increasing lipolysis through the cAMP‐PKA pathway.”

What the sources say

• Not checked yetcites [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

In the paper

“Apart from its role in the regulation of food intake described above, leptin can increase energy expenditure by inducing BAT activation.”

What the sources say

• Not checked yetcites [108] Dodd GT, Decherf S, Loh K, Simonds SE, Wiede F, Balland E, Merry TL, Munzberg H, Zhang ZY, Kahn BB et al (2015) Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160: 88–104 source
• Not checked yetcites [109] Dodd GT, Andrews ZB, Simonds SE, Michael NJ, DeVeer M, Bruning JC, Spanswick D, Cowley MA, Tiganis T (2017) A hypothalamic phosphatase switch coordinates energy expenditure with feeding. Cell Metab 26: 375–393 e7 source

In the paper

“The ensemble of muscle‐derived peptides and proteins, currently referred to as myokines, is at least in part, responsible for exercise whole‐body health benefits.”

What the sources say

• Not checked yetcites [11] Giudice J, Taylor JM (2017) Muscle as a paracrine and endocrine organ. Curr Opin Pharmacol 34: 49–55 source

In the paper

“Irisin was shown to trigger WAT remodeling by increasing p38 signaling, UCP1 expression, and therefore browning 115, 116.”

What the sources say

• Not checked yetcites [115] Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ et al (2012) A PGC1‐alpha‐dependent myokine that drives brown‐fat‐like development of white fat and thermogenesis. Nature 481: 463–468 source
• Not checked yetcites [116] Zhang Y, Li R, Meng Y, Li S, Donelan W, Zhao Y, Qi L, Zhang M, Wang X, Cui T et al (2014) Irisin stimulates browning of white adipocytes through mitogen‐activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes 63: 514–525 source

In the paper

“Importantly, it is worth noting that the production of “positive” myokines is as much promoted by physical exercise as it is repressed by physical inactivity, highlighting the importance of lifestyle for healthspan 112.”

What the sources say

• Not checked yetcites [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

In the paper

“Recent analyses of muscle secretomes revealed that aerobic exercise or strength training trigger the secretion of numerous myokines 11.”

What the sources say

• Not checked yetcites [11] Giudice J, Taylor JM (2017) Muscle as a paracrine and endocrine organ. Curr Opin Pharmacol 34: 49–55 source

In the paper

“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.”

What the sources say

• Not checked yetcites [11] Giudice J, Taylor JM (2017) Muscle as a paracrine and endocrine organ. Curr Opin Pharmacol 34: 49–55 source
• Not checked yetcites [17] Pedersen BK, Febbraio MA (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8: 457–465 source

In the paper

“Moreover, irisin of central (hippocampal) and peripheral origin has been recently shown to promote an increase in cognitive function 119, further highlighting the potential benefits of exercise on healthspan.”

What the sources say

• Not checked yetcites [119] Lourenco MV, Frozza RL, de Freitas GB, Zhang H, Kincheski GC, Ribeiro FC, Goncalves RA, Clarke JR, Beckman D, Staniszewski A et al (2019) Exercise‐linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Nat Med 25: 165–175 source

In the paper

“Overall in this section, we described how, in order to satisfy the energy demands generated by exercise, muscle communicates with other organs to ensure energy substrate availability.”

In the paper

“Obesity is also accompanied by an increased NPY expression in the ARC.”

What the sources say

• Not checked yetcites [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

In the paper

“In obesity conditions, pathological leptin signaling also contributes to sustained hepatic glucose production, due to abnormal activation of ARC neurons 128.”

What the sources say

• Not checked yetcites [128] Balland E, Chen W, Dodd GT, Conductier G, Coppari R, Tiganis T, Cowley MA (2019) Leptin signaling in the arcuate nucleus reduces insulin's capacity to suppress hepatic glucose production in obese mice. Cell Rep 26: 346–355 e3 source

In the paper

“Importantly, during exercise, muscle can signal directly to the brain to promote cognitive function, providing an additional support for lifestyle modifications including an increase in physical activity 125.”

What the sources say

• Not checked yetcites [125] Suzuki WA (2016) How body affects brain. Cell Metab 24: 192–193 source

In the paper

“Moreover, under cold exposure, when shivering thermogenesis is induced, FGF21 can synergize with irisin to promote BAT non‐shivering thermogenesis 118.”

What the sources say

• Not checked yetcites [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

In the paper

“An example of the use of novel strategies for the discovery of endocrine interactions with physiological relevance for whole‐body metabolism is the recent discovery of a novel adipokine, mouse lipocalin 5 (Lcn5; LCN6 in humans), that has the ability to promote insulin sensitivity by enhancing muscle mitochondrial function 135.”

What the sources say

• Not checked yetcites [135] Seldin MM, Koplev S, Rajbhandari P, Vergnes L, Rosenberg GM, Meng Y, Pan C, Phuong TMN, Gharakhanian R, Che N et al (2018) A strategy for discovery of endocrine interactions with application to whole‐body metabolism. Cell Metab 27: 1138–1155 e6 source

In the paper

“Circulating asprosin levels are higher in obese humans and mice 60.”

What the sources say

• Not checked yetcites [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

In the paper

“In pathological conditions of obesity, the reduction in CSF levels of adiponectin that is accompanied by feeding is lost, thus maintaining a “high food intake behavior” even in conditions that are not of energy scarcity (high energy conditions) 56.”

What the sources say

• Not checked yetcites [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

In the paper

“Alternatively, mouse models of obesity and unhealthy obese individuals exhibit lower circulating levels of adiponectin.”

What the sources say

• Not checked yetcites [12] Fasshauer M, Bluher M (2015) Adipokines in health and disease. Trends Pharmacol Sci 36: 461–470 source
• Not checked yetcites [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

In the paper

“Due to the orexigenic effects of this hormone, this alteration could contribute to the difficulties to obtain a voluntary reduction in food intake in obese patients 60.”

What the sources say

• Not checked yetcites [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

In the paper

“This observation suggests that high plasma asprosin may contribute to the onset of hyperglycemia and insulin resistance in mice and humans.”

What the sources say

• Not checked yetcites [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

In the paper

“Moreover, the improvement of the metabolic phenotype of obese insulin‐resistant mice when using an antibody to sequester circulating asprosin makes this novel adipokine a potential therapeutic target against diabetes 59.”

What the sources say

• Not checked yetcites [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

In the paper

“This finding that adiponectin levels are proportional to metabolic fitness has prompted the use of recombinant adiponectin and other adiponectin receptor agonists in several mouse models of obesity.”

What the sources say

• Not checked yetcites [12] Fasshauer M, Bluher M (2015) Adipokines in health and disease. Trends Pharmacol Sci 36: 461–470 source
• Not checked yetcites [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

In the paper

“Importantly, adiponectin has been shown to improve the metabolic profile in leptin deficient ob/ob mice by overall increasing energy expenditure, despite not triggering a reduction in food intake 131.”

What the sources say

• Not checked yetcites [131] Qi Y, Takahashi N, Hileman SM, Patel HR, Berg AH, Pajvani UB, Scherer PE, Ahima RS (2004) Adiponectin acts in the brain to decrease body weight. Nat Med 10: 524–529 source

In the paper

“Of note, despite showing significant effects in promoting muscle mitochondrial function in cellular models, the effects of the novel adipokine Lcn5 in promoting glucose and insulin sensitivity in vivo were more pronounced in a high‐fat high‐sucrose (HF‐HS) model.”

What the sources say

• Not checked yetcites [135] Seldin MM, Koplev S, Rajbhandari P, Vergnes L, Rosenberg GM, Meng Y, Pan C, Phuong TMN, Gharakhanian R, Che N et al (2018) A strategy for discovery of endocrine interactions with application to whole‐body metabolism. Cell Metab 27: 1138–1155 e6 source

In the paper

“However, it is worth noting that Lcn5 overexpression had positive effects on the metabolic status whether at the beginning or after several weeks of HF‐HS diet 135.”

What the sources say

• Not checked yetcites [135] Seldin MM, Koplev S, Rajbhandari P, Vergnes L, Rosenberg GM, Meng Y, Pan C, Phuong TMN, Gharakhanian R, Che N et al (2018) A strategy for discovery of endocrine interactions with application to whole‐body metabolism. Cell Metab 27: 1138–1155 e6 source

In the paper

“In conditions of insulin resistance, WAT secretome is substantially altered and includes a broad range of proinflammatory factors, such as TNF‐α, IL‐6, interleukin 8 (IL‐8), and interleukin 1β (IL‐1B) and monocyte chemotactic protein 1 (MCP1) 12.”

What the sources say

• Not checked yetcites [12] Fasshauer M, Bluher M (2015) Adipokines in health and disease. Trends Pharmacol Sci 36: 461–470 source

In the paper

“The secretion of these proinflammatory cytokines and chemokines, as well as the secretion of other adipokines like retinol binding protein 4 (RBP4) 141, 142, is now well admitted to contribute to the onset of the physiological alterations accompanying obesity 12.”

What the sources say

• Not checked yetcites [12] Fasshauer M, Bluher M (2015) Adipokines in health and disease. Trends Pharmacol Sci 36: 461–470 source
• Not checked yetcites [141] Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB (2005) Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436: 356–362 source
• Not checked yetcites [142] Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, Wason CJ, Oberbach A, Jansson PA, Smith U et al (2006) Retinol‐binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med 354: 2552–2563 source

In the paper

“Myostatin was first described to be secreted during development to limit muscle growth 143, but is also known today to be produced in adults 144, and to promote muscle atrophy, in part by inhibiting AKT and mTOR signaling.”

What the sources say

• Not checked yetcites [144] Argiles JM, Orpi M, Busquets S, Lopez‐Soriano FJ (2012) Myostatin: more than just a regulator of muscle mass. Drug Discov Today 17: 702–709 source

In the paper

“Chronically, high levels of circulating IL‐6 in response to HFD contribute to obesity by promoting macrophage recruitment to WAT 140.”

What the sources say

• Not checked yetcites [140] Kraakman MJ, Kammoun HL, Allen TL, Deswaerte V, Henstridge DC, Estevez E, Matthews VB, Neill B, White DA, Murphy AJ et al (2015) Blocking IL‐6 trans‐signaling prevents high‐fat diet‐induced adipose tissue macrophage recruitment but does not improve insulin resistance. Cell Metab 21: 403–416 source

In the paper

“Alterations in myokine production associated with physical inactivity may also mediate the onset of obesity.”

What the sources say

• Not checked yetcites [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

In the paper

“Moreover, a reduced incretin effect is seen in subjects with type 2 diabetes (T2D) and obesity.”

What the sources say

• Not checked yetcites [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

In the paper

“The use of unbiased genetic and proteomic approaches also allowed the identification of a novel secreted protein, Meteorin‐like (Metrnl), that can be produced by exercising muscle and cold exposed adipose tissue.”

What the sources say

• Not checked yetcites [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

In the paper

“Indeed, ghrelin has lower orexigenic activity in DIO rodents due to a reduction in activation and plasticity of NPY/AgRP neurons 138.”

What the sources say

• Not checked yetcites [138] Briggs DI, Enriori PJ, Lemus MB, Cowley MA, Andrews ZB (2010) Diet‐induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons. Endocrinology 151: 4745–4755 source

In the paper

“Overall, the finding that inter‐organ communication is altered in conditions of obesity (Table 1) has gathered increasing attention for researchers aiming to manipulate those preestablished axes to counteract metabolic alterations.”

In the paper

“Indeed, leptin therapy alone has failed to induce significant weight loss or insulin sensitization 149, 150.”

What the sources say

• Not checked yetcites [149] Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P et al (1999) Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose‐escalation trial. JAMA 282: 1568–1575 source
• Not checked yetcites [150] Hukshorn CJ, Saris WH, Westerterp‐Plantenga MS, Farid AR, Smith FJ, Campfield LA (2000) Weekly subcutaneous pegylated recombinant native human leptin (PEG‐OB) administration in obese men. J Clin Endocrinol Metab 85: 4003–4009 source

In the paper

“However, myostatin‐deficient mice also develop insulin resistance via alterations in AMPK activity 148, highlighting the need to determine the exact effects of myostatin signaling, as well as of other myokines correlating with obesity, in whole‐body energy homeostasis 112.”

What the sources say

• Not checked yetcites [148] Zhang C, McFarlane C, Lokireddy S, Bonala S, Ge X, Masuda S, Gluckman PD, Sharma M, Kambadur R (2011) Myostatin‐deficient mice exhibit reduced insulin resistance through activating the AMP‐activated protein kinase signalling pathway. Diabetologia 54: 1491–1501 source

In the paper

“Myostatin was first described to be secreted during development to limit muscle growth 143, but is also known today to be produced in adults 144, and to promote muscle atrophy, in part by inhibiting AKT and mTOR signaling.”

What the sources say

• Not checked yetcites [144] Argiles JM, Orpi M, Busquets S, Lopez‐Soriano FJ (2012) Myostatin: more than just a regulator of muscle mass. Drug Discov Today 17: 702–709 source

In the paper

“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.”

What the sources say

• Not checked yetcites [145] LeBrasseur NK, Schelhorn TM, Bernardo BL, Cosgrove PG, Loria PM, Brown TA (2009) Myostatin inhibition enhances the effects of exercise on performance and metabolic outcomes in aged mice. J Gerontol A Biol Sci Med Sci 64: 940–948 source

In the paper

“More recently, population‐based methods taking advantage of the natural variations between transcript levels within strains of a mouse reference population have been used to identify new inter‐organ communication networks in metabolism 135.”

What the sources say

• Not checked yetcites [135] Seldin MM, Koplev S, Rajbhandari P, Vergnes L, Rosenberg GM, Meng Y, Pan C, Phuong TMN, Gharakhanian R, Che N et al (2018) A strategy for discovery of endocrine interactions with application to whole‐body metabolism. Cell Metab 27: 1138–1155 e6 source

In the paper

“More recently, GLP‐1 and glucagon receptor co‐agonists have been successfully used in preclinical studies for metabolic diseases 158, but additional research is necessary to demonstrate their efficacy in humans.”

What the sources say

• Not checked yetcites [158] Seghieri M, Christensen AS, Andersen A, Solini A, Knop FK, Vilsboll T (2018) Future perspectives on GLP‐1 receptor agonists and GLP‐1/glucagon receptor co‐agonists in the treatment of NAFLD. Front Endocrinol (Lausanne) 9: 649 source

In the paper

“Due to the potential therapeutic effect of increasing overall energy consumption by promoting brite and brown adipose cell metabolism, recent research has focused on the identification of natural hormones or compounds with the capability to promote thermogenic function, such as FGF21, irisin, and BAs 151.”

What the sources say

• Not checked yetcites [151] Villarroya F, Vidal‐Puig A (2013) Beyond the sympathetic tone: the new brown fat activators. Cell Metab 17: 638–643 source

In the paper

“Finally, despite evidence that irisin treatment can positively affect glucose and lipid metabolism in mice, no real consensus exists as of yet concerning the link between irisin and the metabolic syndrome in humans, and no irisin analog has been used for studies in humans 117.”

What the sources say

• Not checked yetcites [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

In the paper

“This bioinformatic‐based approach allowed for the identification of Lcn5, an adipokine that promotes muscle mitochondrial function, and of Notum, a hepatokine that promotes WAT browning and BAT thermogenesis 135.”

What the sources say

• Not checked yetcites [135] Seldin MM, Koplev S, Rajbhandari P, Vergnes L, Rosenberg GM, Meng Y, Pan C, Phuong TMN, Gharakhanian R, Che N et al (2018) A strategy for discovery of endocrine interactions with application to whole‐body metabolism. Cell Metab 27: 1138–1155 e6 source

In the paper

“In addition, Mills and colleagues demonstrated that succinate accumulates in BAT upon cold exposure and favors thermogenesis in an UCP1‐dependent manner 164.”

What the sources say

• Not checked yetcites [164] Mills EL, Pierce KA, Jedrychowski MP, Garrity R, Winther S, Vidoni S, Yoneshiro T, Spinelli JB, Lu GZ, Kazak L et al (2018) Accumulation of succinate controls activation of adipose tissue thermogenesis. Nature 560: 102–106 source

In the paper

“Diet composition, nutrient availability and metabolic status can also modulate pharmacological treatments.”

What the sources say

• Not checked yetcites [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

In the paper

“Furthermore, gut microbiota has been described in the past two decades as a very important player in the regulation of whole‐body energy homeostasis, in response to diverse stimuli such as cold 165, 166, nutrition 167, 168, or fasting/feeding cycles 168, 169, 170, through the production of mediators such as short chain fatty acids (SCFAs) and secondary BAs 167, 169.”

What the sources say

• Not checked yetcites [165] Chevalier C, Stojanovic O, Colin DJ, Suarez‐Zamorano N, Tarallo V, Veyrat‐Durebex C, Rigo D, Fabbiano S, Stevanovic A, Hagemann S et al (2015) Gut microbiota orchestrates energy homeostasis during cold. Cell 163: 1360–1374 source
• Not checked yetcites [166] Li B, Li L, Li M, Lam SM, Wang G, Wu Y, Zhang H, Niu C, Zhang X, Liu X et al (2019) Microbiota depletion impairs thermogenesis of brown adipose tissue and browning of white adipose tissue. Cell Rep 26: 2720–2737 e5 source
• Not checked yetcites [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
• Not checked yetcites [168] Zmora N, Suez J, Elinav E (2019) You are what you eat: diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol 16: 35–56 source
• Not checked yetcites [169] Cani PD, Van Hul M, Lefort C, Depommier C, Rastelli M, Everard A (2019) Microbial regulation of organismal energy homeostasis. Nat Metab 1: 34–46 source
• Not checked yetcites [170] Li G, Xie C, Lu S, Nichols RG, Tian Y, Li L, Patel D, Ma Y, Brocker CN, Yan T et al (2017) Intermittent fasting promotes white adipose browning and decreases obesity by shaping the gut microbiota. Cell Metab 26: 801 source

In the paper

“Indeed, it is well known that fasting/feeding cycles can influence drug efficiency 172; however, the mechanism behind this observation remains mostly unknown.”

What the sources say

• Not checked yetcites [172] Charman WN, Porter CJ, Mithani S, Dressman JB (1997) Physiochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. J Pharm Sci 86: 269–282 source

In the paper

“A similar approach, based on a transcriptomics data mining strategy, was used to identify CXCL14, a novel batokine that promotes thermogenesis by facilitating the recruitment of anti‐inflammatory macrophages to BAT 161.”

What the sources say

• Not checked yetcites [161] Cereijo R, Gavalda‐Navarro A, Cairo M, Quesada‐Lopez T, Villarroya J, Moron‐Ros S, Sanchez‐Infantes D, Peyrou M, Iglesias R, Mampel T et al (2018) CXCL14, a brown adipokine that mediates brown‐fat‐to‐macrophage communication in thermogenic adaptation. Cell Metab 28: 750–763 e6 source

In the paper

“For instance, BAT‐produced mir‐99b loaded exosomes contribute to the repression of hepatic FGF21 expression 171.”

What the sources say

• Not checked yetcites [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