Inter‐organ communication: a gatekeeper for metabolic health

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [3] Myers Jr MG, Olson DP (2012) Central nervous system control of metabolism. Nature 491: 357–363 source
• Not checked yetcites [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

In the paper

“Indeed, leptin suppresses food intake and the production of adrenal corticosteroids while promoting energy expenditure and decreasing insulin secretion 38, 39.”

What the sources say

• Not checked yetcites [38] Pan WW, Myers Jr MG (2018) Leptin and the maintenance of elevated body weight. Nat Rev Neurosci 19: 95–105 source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“FGF19 then signals to the liver and induces a feedback repression of hepatic BA synthesis 42.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Indeed, LEAP2 can fully blunt GHSR activation by ghrelin, thus reducing food intake and growth hormone (GH) release 47.”

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

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“Importantly, Fgf15 can also signal through the brain to modulate glucose homeostasis 45 and glucagon secretion 46.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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.”

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

“Plasma concentrations of ghrelin are high during fasting and decrease in the postprandial state 48.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [64] BonDurant LD, Potthoff MJ (2018) Fibroblast growth factor 21: a versatile regulator of metabolic homeostasis. Annu Rev Nutr 38: 173–196 source
• Not checked yetcites [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

In the paper

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

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 process is independent from glucagon receptor signaling and from the β‐adrenergic receptor 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

“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”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“The central administration of orexin peptide has been described to stimulate BAT activation and therefore thermogenesis 77.”

What the sources say

• Not checked yetcites [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

In the paper

“Interestingly, BMP8b can also be produced in BAT and promote NE signaling locally, activating the MAPK pathway and lipolysis in brown adipocytes 80.”

What the sources say

• Not checked yetcites [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

In the paper

“Mammals have BAT, a highly specialized tissue that functions to produce heat 73.”

What the sources say

• Not checked yetcites [73] Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84: 277–359 source

In the paper

“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.”

What the sources say

• Not checked yetcites [76] Zhang W, Bi S (2015) Hypothalamic regulation of brown adipose tissue thermogenesis and energy homeostasis. Front Endocrinol (Lausanne) 6: 136

In the paper

“However, it is denser in specific regions of subcutaneous (or inguinal) WAT and can be increased in response to cold 70, 71.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“BAT is especially abundant in hibernating mammals 74 , but can also be found in adult humans 75.”

What the sources say

• Not checked yetcites [74] Gesta S, Tseng YH, Kahn CR (2007) Developmental origin of fat: tracking obesity to its source. Cell 131: 242–256 source
• Not checked yetcites [75] Cypess AM, Kahn CR (2010) Brown fat as a therapy for obesity and diabetes. Curr Opin Endocrinol Diabetes Obes 17: 143–149 source

In the paper

“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.”

What the sources say

• Not checked yetcites [73] Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84: 277–359 source
• Not checked yetcites [85] Fedorenko A, Lishko PV, Kirichok Y (2012) Mechanism of fatty‐acid‐dependent UCP1 uncoupling in brown fat mitochondria. Cell 151: 400–413 source

In the paper

“Under cold exposure, FGF21 can be secreted by BAT and WAT, have a paracrine effect, and stimulate the expression of thermogenic genes 91.”

What the sources say

• Not checked yetcites [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

In the paper

“Some teams have reported that FGF21 knockout mice have impaired adaptation to chronic cold exposure and decreased browning of WAT 92.”

What the sources say

• Not checked yetcites [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

In the paper

“Brite adipocytes can express UCP1 and, as such, can participate in the maintenance of body temperature 90.”

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

“However, others have shown that the lack of FGF21 in long‐term cold adaptation does not impair the thermogenic response of mice 93.”

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“These mice show neglectable browning and exhibit reduced cold tolerance due to reduced adipose mitochondrial fusion 98.”

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

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [104] Kelsey R (2018) BAT is involved in control of satiation. Nat Rev Endocrinol 15: 1 source

In the paper

“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.”

In the paper

“Interestingly, secretin can stimulate BAT thermogenesis in a non‐sympathetic manner and contribute to satiation.”

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

“Moreover, secretin treatment increases the expression of the anorexigenic proopiomelanocortin (POMC) peptide in the hypothalamus and therefore reduces food intake 107.”

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

“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.”

In the paper

“Irisin can also increase muscle oxidative metabolism and substrate (glucose and fatty acid) uptake, and reduce hepatic glucose output 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

“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.”

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

“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, 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.”

What the sources say

• 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
• Not checked yetcites [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

In the paper

“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.”

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

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Interestingly, cold‐induced muscle shivering can increase circulating irisin levels and promote brown fat thermogenesis 118 (Fig 3).”

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

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

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

In the paper

“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.”

What the sources say

• Not checked yetcites [123] Virtanen KA (2014) BAT thermogenesis: linking shivering to exercise. Cell Metab 19: 352–354 source
• Not checked yetcites [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

In the paper

“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.”

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

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“So far, the activation of adiponectin signaling has improved glucose tolerance, insulin sensitivity, and longevity in mice 12, 130.”

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

“Interestingly, postprandial glucagon‐like peptide‐1 (GLP‐1) secretion is increased in obese patients following bariatric surgery and correlates with weight loss maintenance 139.”

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

“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.”

In the paper

“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.”

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

“However, serum Metrnl levels are decreased in patients with T2D and inversely correlate with fasting glucose levels 137.”

What the sources say

• Not checked yetcites [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

In the paper

“Metrnl promotes adipose tissue browning by recruiting IL‐4 and IL‐13 producing eosinophils and thus promoting anti‐inflammatory macrophage activation 136.”

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

“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.”

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

“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 [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 yetcites [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

In the paper

“Adiponectin receptor analogs have successfully been used in preclinical mouse models 130, but have not yet been used in human patients.”

What the sources say

• 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

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Moreover, GLP‐1Ras improve glycemic control and reduce liver inflammation and fibrosis 157.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [160] Lindskog C (2015) The potential clinical impact of the tissue‐based map of the human proteome. Expert Rev Proteomics 12: 213–215 source

In the paper

“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.”

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

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

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

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

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

“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.”

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
• Not checked yetcites [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
• Not checked yetcites [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