The secretory function of adipose tissues in metabolic regulation
Received date: 01 Nov 2023
Revised date: 04 Jan 2024
Accepted date: 19 Jan 2024
Published date: 22 Jul 2024
Copyright
In addition to their pivotal roles in energy storage and expenditure, adipose tissues play a crucial part in the secretion of bioactive molecules, including peptides, lipids, metabolites, and extracellular vesicles, in response to physiological stimulation and metabolic stress. These secretory factors, through autocrine and paracrine mechanisms, regulate various processes within adipose tissues. These processes include adipogenesis, glucose and lipid metabolism, inflammation, and adaptive thermogenesis, all of which are essential for the maintenance of the balance and functionality of the adipose tissue micro-environment. A subset of these adipose-derived secretory factors can enter the circulation and target the distant tissues to regulate appetite, cognitive function, energy expenditure, insulin secretion and sensitivity, gluconeogenesis, cardiovascular remodeling, and exercise capacity. In this review, we highlight the role of adipose-derived secretory factors and their signaling pathways in modulating metabolic homeostasis. Furthermore, we delve into the alterations in both the content and secretion processes of these factors under various physiological and pathological conditions, shedding light on potential pharmacological treatment strategies for related diseases.
Key words: adipokines; autocrine; paracrine; endocrine; metabolic regulation
Yang Liu , Shu-Wen Qian , Yan Tang , Qi-Qun Tang . The secretory function of adipose tissues in metabolic regulation[J]. Life Metabolism, 2024 , 3(2) : loae003 . DOI: 10.1093/lifemeta/loae003
1 |
Auger C , Kajimura S . Adipose tissue remodeling in pathophysiology. Annu Rev Pathol 2023; 18: 71- 93.
|
2 |
Sakers A , De Siqueira MK , Seale P et al. Adipose-tissue plasticity in health and disease. Cell 2022; 185: 419- 46.
|
3 |
Chouchani ET , Kajimura S . Metabolic adaptation and maladaptation in adipose tissue. Nat Metab 2019; 1: 189- 200.
|
4 |
Chouchani ET , Kazak L , Spiegelman BM . New advances in adaptive thermogenesis: UCP1 and beyond. Cell Metab 2019; 29: 27- 37.
|
5 |
Shamsi F , Wang CH , Tseng YH . The evolving view of thermogenic adipocytes—ontogeny, niche and function. Nat Rev Endocrinol 2021; 17: 726- 44.
|
6 |
Wang W , Seale P . Control of brown and beige fat development. Nat Rev Mol Cell Biol 2016; 17: 691- 702.
|
7 |
Becher T , Palanisamy S , Kramer DJ et al. Brown adipose tissue is associated with cardiometabolic health. Nat Med 2021; 27: 58- 65.
|
8 |
Fasshauer M , Bluher M . Adipokines in health and disease. Trends Pharmacol Sci 2015; 36: 461- 70.
|
9 |
Scheja L , Heeren J . The endocrine function of adipose tissues in health and cardiometabolic disease. Nat Rev Endocrinol 2019; 15: 507- 24.
|
10 |
Cook KS , Min HY , Johnson D et al. Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science 1987; 237: 402- 5.
|
11 |
Siiteri PK . Adipose tissue as a source of hormones. Am J Clin Nutr 1987; 45: 277- 82.
|
12 |
Zhang Y , Proenca R , Maffei M et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425- 32.
|
13 |
Maffei M , Halaas J , Ravussin E et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995; 1: 1155- 61.
|
14 |
Rosenbaum M , Nicolson M , Hirsch J et al. Effects of gender, body composition, and menopause on plasma concentrations of leptin. J Clin Endocrinol Metab 1996; 81: 3424- 7.
|
15 |
Guo KY , Halo P , Leibel RL , Zhang Y . Effects of obesity on the relationship of leptin mRNA expression and adipocyte size in anatomically distinct fat depots in mice. Am J Physiol Regul Integr Comp Physiol 2004; 287: R112- 9.
|
16 |
Montague CT , Prins JB , Sanders L et al. Depot- and sexspecific differences in human leptin mRNA expression: implications for the control of regional fat distribution. Diabetes 1997; 46: 342- 7.
|
17 |
Van Harmelen V , Reynisdottir S , Eriksson P et al. Leptin secretion from subcutaneous and visceral adipose tissue in women. Diabetes 1998; 47: 913- 7.
|
18 |
Dahlmann S , Bressem K , Bashian B et al. Sex differences in renal cell carcinoma: the importance of body composition. Ann Surg Oncol 2023; 30: 1269- 76.
|
19 |
Ogawa Y , Masuzaki H , Isse N et al. Molecular cloning of rat obese cDNA and augmented gene expression in genetically obese Zucker fatty (fa/fa) rats. J Clin Invest 1995; 96: 1647- 52.
|
20 |
Li H , Matheny M , Nicolson M et al. Leptin gene expression increases with age independent of increasing adiposity in rats. Diabetes 1997; 46: 2035- 9.
|
21 |
Zhang Y , Hufnagel C , Eiden S et al. Mechanisms for LEPR-mediated regulation of leptin expression in brown and white adipocytes in rat pups. Physiol Genomics 2001; 4: 189- 99.
|
22 |
Zhang Y , Chua S Jr . Leptin function and regulation. Compr Physiol 2017; 8: 351- 69.
|
23 |
Peelman F , Zabeau L , Moharana K et al. 20 years of leptin: insights into signaling assemblies of the leptin receptor. J Endocrinol 2014; 223: T9- 23.
|
24 |
Tu H , Hsuchou H , Kastin AJ . Unique leptin trafficking by a tailless receptor. FASEB J 2010; 24: 2281- 91.
|
25 |
Tu H , Kastin AJ , Hsuchou H . Soluble receptor inhibits leptin transport. J Cell Physiol 2008; 214: 301- 5.
|
26 |
Morris DL , Rui L . Recent advances in understanding leptin signaling and leptin resistance. Am J Physiol Endocrinol Metab 2009; 297: E1247- 59.
|
27 |
Baldini G , Phelan KD . The melanocortin pathway and control of appetite-progress and therapeutic implications. J Endocrinol 2019; 241: R1- 33.
|
28 |
Gropp E , Shanabrough M , Borok E et al. Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci 2005; 8: 1289- 91.
|
29 |
Obradovic M , Sudar-Milovanovic E , Soskic S et al. Leptin and obesity: role and clinical implication. Front Endocrinol (Lausanne) 2021; 12: 585887.
|
30 |
Wang P , Loh KH , Wu M et al. A leptin-BDNF pathway regulating sympathetic innervation of adipose tissue. Nature 2020; 583: 839- 44.
|
31 |
Pico C , Palou M , Pomar CA et al. Leptin as a key regulator of the adipose organ. Rev Endocr Metab Disord 2022; 23: 13- 30.
|
32 |
Farooqi IS , Jebb SA , Langmack G et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341: 879- 84.
|
33 |
Heymsfield SB , Greenberg AS , Fujioka K et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999; 282: 1568- 75.
|
34 |
Cui H , Lopez M , Rahmouni K . The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nat Rev Endocrinol 2017; 13: 338- 51.
|
35 |
Knight ZA , Hannan KS , Greenberg ML et al. Hyperleptinemia is required for the development of leptin resistance. PLoS One 2010; 5: e11376.
|
36 |
Koch CE , Lowe C , Pretz D et al. High-fat diet induces leptin resistance in leptin-deficient mice. J Neuroendocrinol 2014; 26: 58- 67.
|
37 |
Zhao S , Zhu Y , Schultz RD et al. Partial leptin reduction as an insulin sensitization and weight loss strategy. Cell Metab 2019; 30: 706- 19.e6.
|
38 |
Straub LG , Scherer PE . Metabolic messengers: adiponectin. Nat Metab 2019; 1: 334- 9.
|
39 |
Wang ZV , Scherer PE . Adiponectin, the past two decades. J Mol Cell Biol 2016; 8: 93- 100.
|
40 |
Pischon T , Hotamisligil GS , Rimm EB . Adiponectin: stability in plasma over 36 hours and within-person variation over 1 year. Clin Chem 2003; 49: 650- 2.
|
41 |
Pajvani UB , Du X , Combs TP et al. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin: implications for metabolic regulation and bioactivity. J Biol Chem 2003; 278: 9073- 85.
|
42 |
Arita Y , Kihara S , Ouchi N et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999; 257: 79- 83.
|
43 |
Spranger J , Kroke A , Möhlig M et al. Adiponectin and protection against type 2 diabetes mellitus. Lancet 2003; 361: 226- 8.
|
44 |
Ouchi N , Kihara S , Arita Y et al. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 1999; 100: 2473- 6.
|
45 |
Pischon T , Girman CJ , Hotamisligil GS et al. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 2004; 291: 1730- 7.
|
46 |
Maeda N , Shimomura I , Kishida K et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002; 8: 731- 7.
|
47 |
Xia JY , Sun K , Hepler C et al. Acute loss of adipose tissue-derived adiponectin triggers immediate metabolic deterioration in mice. Diabetologia 2018; 61: 932- 41.
|
48 |
Berg AH , Combs TP , Du X et al. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001; 7: 947- 53.
|
49 |
Yamauchi T , Kamon J , Waki H et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7: 941- 6.
|
50 |
Tomas E , Tsao TS , Saha AK et al. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci U S A 2002; 99: 16309- 13.
|
51 |
Yamauchi T , Kamon J , Minokoshi Y et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002; 8: 1288- 95.
|
52 |
Kersten S , Desvergne B , Wahli W . Roles of PPARs in health and disease. Nature 2000; 405: 421- 4.
|
53 |
Qi Y , Takahashi N , Hileman SM et al. Adiponectin acts in the brain to decrease body weight. Nat Med 2004; 10: 524- 9.
|
54 |
Yamauchi T , Kamon J , Ito Y et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003; 423: 762- 9.
|
55 |
Tsuchida A , Yamauchi T , Ito Y et al. Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity. J Biol Chem 2004; 279: 30817- 22.
|
56 |
Yamauchi T , Nio Y , Maki T et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 2007; 13: 332- 9.
|
57 |
Holland WL , Xia JY , Johnson JA et al. Inducible overexpression of adiponectin receptors highlight the roles of adiponectin-induced ceramidase signaling in lipid and glucose homeostasis. Mol Metab 2017; 6: 267- 75.
|
58 |
Iwabu M , Okada-Iwabu M , Tanabe H et al. AdipoR agonist increases insulin sensitivity and exercise endurance in AdipoR-humanized mice. Commun Biol 2021; 4: 45.
|
59 |
Okada-Iwabu M , Yamauchi T , Iwabu M et al. A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 2013; 503: 493- 9.
|
60 |
Xu H , Zhao Q , Song N et al. AdipoR1/AdipoR2 dual agonist recovers nonalcoholic steatohepatitis and related fibrosis via endoplasmic reticulum-mitochondria axis. Nat Commun 2020; 11: 5807.
|
61 |
Vasiliauskaite-Brooks I , Sounier R , Rochaix P et al. Structural insights into adiponectin receptors suggest ceramidase activity. Nature 2017; 544: 120- 3.
|
62 |
Chaurasia B , Summers SA . Ceramides—lipotoxic inducers of metabolic disorders. Trends Endocrinol Metab 2015; 26: 538- 50.
|
63 |
Holland WL , Miller RA , Wang ZV et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 2011; 17: 55- 63.
|
64 |
Holland WL , Scherer PE . Structural biology: receptors grease the metabolic wheels. Nature 2017; 544: 42- 4.
|
65 |
Morcos YAT , Lütke S , Tenbieg A et al. Sensitive asprosin detection in clinical samples reveals serum/saliva correlation and indicates cartilage as source for serum asprosin. Sci Rep 2022; 12: 1340.
|
66 |
Romere C , Duerrschmid C , Bournat J et al. Asprosin, a fasting-induced glucogenic protein hormone. Cell 2016; 165: 566- 79.
|
67 |
Ugur K , Aydin S . Saliva and blood asprosin hormone concentration associated with obesity. Int J Endocrinol 2019; 2019: 2521096.
|
68 |
Duerrschmid C , He Y , Wang C et al. Asprosin is a centrally acting orexigenic hormone. Nat Med 2017; 23: 1444- 53.
|
69 |
Li E , Shan H , Chen L et al. OLFR734 mediates glucose metabolism as a receptor of asprosin. Cell Metab 2019; 30: 319- 28.e8.
|
70 |
Mishra I , Xie WR , Bournat JC et al. Protein tyrosine phosphatase receptor δ serves as the orexigenic asprosin receptor. Cell Metab 2022; 34: 549- 63.e8.
|
71 |
Feng B , Liu H , Mishra I et al. Asprosin promotes feeding through SK channel-dependent activation of AgRP neurons. Sci Adv 2023; 9: eabq6718.
|
72 |
Lee T , Yun S , Jeong JH et al. Asprosin impairs insulin secretion in response to glucose and viability through TLR4/JNK-mediated inflammation. Mol Cell Endocrinol 2019; 486: 96- 104.
|
73 |
Jung TW , Kim H-C , Kim HU et al. Asprosin attenuates insulin signaling pathway through PKCδ-activated ER stress and inflammation in skeletal muscle. J Cell Physiol 2019; 234: 20888- 99.
|
74 |
Miao Y , Qin H , Zhong Y et al. Novel adipokine asprosin modulates browning and adipogenesis in white adipose tissue. J Endocrinol 2021; 249: 83- 93.
|
75 |
Alan M , Gurlek B , Yilmaz A et al. Asprosin: a novel peptide hormone related to insulin resistance in women with polycystic ovary syndrome. Gynecol Endocrinol 2019; 35: 220- 3.
|
76 |
Janoschek R , Hoffmann T , Morcos YAT et al. Asprosin in pregnancy and childhood. Mol Cell Pediatr 2020; 7: 18.
|
77 |
Wang M , Yin C , Wang L et al. Serum asprosin concentrations are increased and associated with insulin resistance in children with obesity. Ann Nutr Metab 2019; 75: 205- 12.
|
78 |
Zhang L , Chen C , Zhou N et al. Circulating asprosin concentrations are increased in type 2 diabetes mellitus and independently associated with fasting glucose and triglyceride. Clin Chim Acta 2019; 489: 183- 8.
|
79 |
Mishra I , Duerrschmid C , Ku Z et al. Asprosin-neutralizing antibodies as a treatment for metabolic syndrome. Elife 2021; 10: e63784.
|
80 |
Wang Y , Qu H , Xiong X et al. Plasma asprosin concentrations are increased in individuals with glucose dysregulation and correlated with insulin resistance and first-phase insulin secretion. Mediators Inflamm 2018; 2018: 9471583.
|
81 |
Funcke JB , Scherer PE . Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication. J Lipid Res 2019; 60: 1648- 84.
|
82 |
Helfer G , Wu QF . Chemerin: a multifaceted adipokine involved in metabolic disorders. J Endocrinol 2018; 238: R79- 94.
|
83 |
De Henau O , Degroot GN , Imbault V et al. Signaling properties of chemerin receptors CMKLR1, GPR1 and CCRL2. PLoS One 2016; 11: e0164179.
|
84 |
Roh SG , Song SH , Choi KC et al. Chemerin—a new adipokine that modulates adipogenesis via its own receptor. Biochem Biophys Res Commun 2007; 362: 1013- 8.
|
85 |
Goralski KB , McCarthy TC , Hanniman EA et al. Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism. J Biol Chem 2007; 282: 28175- 88.
|
86 |
Lin Y , Xiao L , Cai Q et al. The chemerin-CMKLR1 axis limits thermogenesis by controlling a beige adipocyte/IL-33/type 2 innate immunity circuit. Sci Immunol 2021; 6: eabg9698.
|
87 |
Bozaoglu K , Bolton K , McMillan J et al. Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Endocrinology 2007; 148: 4687- 94.
|
88 |
Bozaoglu K , Segal D , Shields KA et al. Chemerin is associated with metabolic syndrome phenotypes in a Mexican-American population. J Clin Endocrinol Metab 2009; 94: 3085- 8.
|
89 |
Chakaroun R , Raschpichler M , Klöting N et al. Effects of weight loss and exercise on chemerin serum concentrations and adipose tissue expression in human obesity. Metabolism 2012; 61: 706- 14.
|
90 |
Molofsky AB , Savage AK , Locksley RM . Interleukin-33 in tissue homeostasis, injury, and inflammation. Immunity 2015; 42: 1005- 19.
|
91 |
Jiang Y , Liu P , Jiao W et al. Gax suppresses chemerin/CMKLR1-induced preadipocyte biofunctions through the inhibition of Akt/mTOR and ERK signaling pathways. J Cell Physiol 2018; 233: 572- 86.
|
92 |
Muruganandan S , Parlee SD , Rourke JL et al. Chemerin, a novel peroxisome proliferator-activated receptor γ (PPARγ) target gene that promotes mesenchymal stem cell adipogenesis. J Biol Chem 2011; 286: 23982- 95.
|
93 |
Ernst MC , Haidl ID , Zúñiga LA et al. Disruption of the chemokine-like receptor-1 (CMKLR1) gene is associated with reduced adiposity and glucose intolerance. Endocrinology 2012; 153: 672- 82.
|
94 |
Ernst MC , Issa M , Goralski KB et al. Chemerin exacerbates glucose intolerance in mouse models of obesity and diabetes. Endocrinology 2010; 151: 1998- 2007.
|
95 |
Rouger L , Denis GR , Luangsay S et al. ChemR23 knockout mice display mild obesity but no deficit in adipocyte differentiation. J Endocrinol 2013; 219: 279- 89.
|
96 |
Takahashi M , Okimura Y , Iguchi G et al. Chemerin regulates β-cell function in mice. Sci Rep 2011; 1: 123.
|
97 |
Enerback S , Jacobsson A , Simpson EM et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 1997; 387: 90- 4.
|
98 |
Feldmann HM , Golozoubova V , Cannon B et al. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab 2009; 9: 203- 9.
|
99 |
Liu X , Rossmeisl M , McClaine J et al. Paradoxical resistance to diet-induced obesity in UCP1-deficient mice. J Clin Invest 2003; 111: 399- 407.
|
100 |
Lowell BB , S-Susulic V , Hamann A et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 1993; 366: 740- 2.
|
101 |
Stern JS , Inokuchi T , Castonguay TW et al. Scapular brown fat removal enhances development of adiposity in cold-exposed obese Zucker rats. Am J Physiol 1984; 247: R918- 26.
|
102 |
Kong X , Yao T , Zhou P et al. Brown adipose tissue controls skeletal muscle function via the secretion of myostatin. Cell Metab 2018; 28: 631- 43.e3.
|
103 |
Ding M , Xu HY , Zhou WY et al. CLCF1 signaling restrains thermogenesis and disrupts metabolic homeostasis by inhibiting mitochondrial biogenesis in brown adipocytes. Proc Natl Acad Sci U S A 2023; 120: e2305717120.
|
104 |
Chen Q , Huang L , Pan D et al. A brown fat-enriched adipokine Adissp controls adipose thermogenesis and glucose homeostasis. Nat Commun 2022; 13: 7633
|
105 |
Wang GX , Zhao XY , Meng ZX et al. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat Med 2014; 20: 1436- 43.
|
106 |
Guo L , Zhang P , Chen Z et al. Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression. J Clin Invest 2017; 127: 4449- 61.
|
107 |
Zhang P , Chen Z , Kuang H et al. Neuregulin 4 suppresses NASHHCC development by restraining tumor-prone liver microenvironment. Cell Metab 2022; 34: 1359- 76.e7.
|
108 |
Shi L , Li Y , Xu X et al. Brown adipose tissue-derived Nrg4 alleviates endothelial inflammation and atherosclerosis in male mice. Nat Metab 2022; 4: 1573- 90.
|
109 |
Henriques F , Bedard AH , Guilherme A et al. Single-cell RNA profiling reveals adipocyte to macrophage signaling sufficient to enhance thermogenesis. Cell Rep 2020; 32: 107998.
|
110 |
Pellegrinelli V , Peirce VJ , Howard L et al. Adipocyte-secreted BMP8b mediates adrenergic-induced remodeling of the neurovascular network in adipose tissue. Nat Commun 2018; 9: 4974.
|
111 |
Rosell M , Kaforou M , Frontini A et al. Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice. Am J Physiol Endocrinol Metab 2014; 306: E945- 64.
|
112 |
Cai C , Lin M , Xu Y et al. Association of circulating neuregulin 4 with metabolic syndrome in obese adults: a cross-sectional study. BMC Med 2016; 14: 165.
|
113 |
Li Y , Jin L , Jiang F et al. Mutations of NRG4 contribute to the pathogenesis of nonalcoholic fatty liver disease and related metabolic disorders. Diabetes 2021; 70: 2213- 24.
|
114 |
Qian S , Tang Y , Tang QQ . Adipose tissue plasticity and the pleiotropic roles of BMP signaling. J Biol Chem 2021; 296: 100678.
|
115 |
Modica S , Wolfrum C . Bone morphogenic proteins signaling in adipogenesis and energy homeostasis. Biochim Biophys Acta 2013; 1831: 915- 23.
|
116 |
Gustafson B , Hammarstedt A , Hedjazifar S et al. BMP4 and BMP antagonists regulate human white and beige adipogenesis. Diabetes 2015; 64: 1670- 81.
|
117 |
Qian SW , Tang Y , Li X et al. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc Natl Acad Sci U S A 2013; 110: E798- 807.
|
118 |
Huang H , Song TJ , Li X et al. BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci U S A 2009; 106: 12670- 5.
|
119 |
Huang HY , Hu LL , Song TJ et al. Involvement of cytoskeleton-associated proteins in the commitment of C3H10T1/2 pluripotent stem cells to adipocyte lineage induced by BMP2/4. Mol Cell Proteomics 2011; 10: M110.002691.
|
120 |
Tang QQ , Otto TC , Lane MD . Commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci U S A 2004; 101: 9607- 11.
|
121 |
Tang Y , Qian SW , Wu MY et al. BMP4 mediates the interplay between adipogenesis and angiogenesis during expansion of subcutaneous white adipose tissue. J Mol Cell Biol 2016; 8: 302- 12.
|
122 |
Hoffmann JM , Grünberg JR , Church C et al. BMP4 gene therapy in mature mice reduces BAT activation but protects from obesity by browning subcutaneous adipose tissue. Cell Rep 2017; 20: 1038- 49.
|
123 |
Modica S , Straub LG , Balaz M et al. Bmp4 promotes a brown to white-like adipocyte shift. Cell Rep 2016; 16: 2243- 58.
|
124 |
Qian SW , Wu MY , Wang YN et al. BMP4 facilitates beige fat biogenesis via regulating adipose tissue macrophages. J Mol Cell Biol 2019; 11: 14- 25.
|
125 |
Nguyen KD , Qiu Y , Cui X et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 2011; 480: 104- 8.
|
126 |
Fischer K , Ruiz HH , Jhun K et al. Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nat Med 2017; 23: 623- 30.
|
127 |
Wang YN , Tang Y , He Z et al. Slit3 secreted from M2-like macrophages increases sympathetic activity and thermogenesis in adipose tissue. Nat Metab 2021; 3: 1536- 51.
|
128 |
Liu Y , Du SY , Ding M et al. The BMP4-Smad signaling pathway regulates hyperandrogenism development in a female mouse model. J Biol Chem 2017; 292: 11740- 50.
|
129 |
Tseng YH , Kokkotou E , Schulz TJ et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 2008; 454: 1000- 4.
|
130 |
Boon MR , van den Berg SAA , Wang Y et al. BMP7 activates brown adipose tissue and reduces diet-induced obesity only at subthermoneutrality. PLoS One 2013; 8: e74083.
|
131 |
Rial-Pensado E , Freire-Agulleiro O , Ríos M et al. Obesity induces resistance to central action of BMP8B through a mechanism involving the BBSome. Mol Metab 2022; 59: 101465.
|
132 |
Urisarri A , González-García I , Estévez-Salguero A et al. BMP8 and activated brown adipose tissue in human newborns. Nat Commun 2021; 12: 5274.
|
133 |
Whittle AJ , Carobbio S , Martins L et al. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 2012; 149: 871- 85.
|
134 |
Vacca M , Leslie J , Virtue S et al. Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis. Nat Metab 2020; 2: 514- 31.
|
135 |
Ying Y , Qi X , Zhao GQ . Induction of primordial germ cells from murine epiblasts by synergistic action of BMP4 and BMP8B signaling pathways. Proc Natl Acad Sci U S A 2001; 98: 7858- 62.
|
136 |
Zhao GQ , Deng K , Labosky PA et al. The gene encoding bone morphogenetic protein 8B is required for the initiation and maintenance of spermatogenesis in the mouse. Genes Dev 1996; 10: 1657- 69.
|
137 |
Wisnieski F , Leal MF , Calcagno DQ et al. BMP8B is a tumor suppressor gene regulated by histone acetylation in gastric cancer. J Cell Biochem 2017; 118: 869- 77.
|
138 |
Grefhorst A , van den Beukel JC , van Houten EL et al. Estrogens increase expression of bone morphogenetic protein 8b in brown adipose tissue of mice. Biol Sex Differ 2015; 6: 7.
|
139 |
Martins L , Seoane-Collazo P , Contreras C et al. A functional link between AMPK and orexin mediates the effect of BMP8B on energy balance. Cell Rep 2016; 16: 2231- 42.
|
140 |
Fisher FM , Maratos-Flier E . Understanding the physiology of FGF21. Annu Rev Physiol 2016; 78: 223- 41.
|
141 |
Kurosu H , Choi M , Ogawa Y et al. Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 2007; 282: 26687- 95.
|
142 |
Abu-Odeh M , Zhang Y , Reilly SM et al. FGF21 promotes thermogenic gene expression as an autocrine factor in adipocytes. Cell Rep 2021; 35: 109331.
|
143 |
Chartoumpekis DV , Habeos IG , Ziros PG et al. Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol Med 2011; 17: 736- 40.
|
144 |
Hondares E , Iglesias R , Giralt A et al. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 2011; 286: 12983- 90.
|
145 |
Fisher FM , Kleiner S , Douris N et al. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 2012; 26: 271- 81.
|
146 |
Huang Z , Zhong L , Lee JTH et al. The FGF21-CCL11 axis mediates beiging of white adipose tissues by coupling sympathetic nervous system to type 2 immunity. Cell Metab 2017; 26: 493- 508.e4.
|
147 |
Chau MD , Gao J , Yang Q et al. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1α pathway. Proc Natl Acad Sci U S A 2010; 107: 12553- 8.
|
148 |
Holland WL , Adams AC , Brozinick JT et al. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab 2013; 17: 790- 7.
|
149 |
Lin Z , Tian H , Lam KS et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab 2013; 17: 779- 89.
|
150 |
Ruan CC , Kong LR , Chen XH et al. A2A receptor activation attenuates hypertensive cardiac remodeling via promoting brown adipose tissue-derived FGF21. Cell Metab 2018; 28: 476- 89.e5.
|
151 |
Keipert S , Kutschke M , Lamp D et al. Genetic disruption of uncoupling protein 1 in mice renders brown adipose tissue a significant source of FGF21 secretion. Mol Metab 2015; 4: 537- 42.
|
152 |
Stanford KI , Middelbeek RJ , Townsend KL et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest 2013; 123: 215- 23.
|
153 |
Cao H , Gerhold K , Mayers JR et al. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 2008; 134: 933- 44.
|
154 |
Rancoule C , Attané C , Grès S et al. Lysophosphatidic acid impairs glucose homeostasis and inhibits insulin secretion in high-fat diet obese mice. Diabetologia 2013; 56: 1394- 402.
|
155 |
Lodhi IJ , Yin L , Jensen-Urstad AP et al. Inhibiting adipose tissue lipogenesis reprograms thermogenesis and PPARγ activation to decrease diet-induced obesity. Cell Metab 2012; 16: 189- 201.
|
156 |
Yore MM , Syed I , Moraes-Vieira PM et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and antiinflammatory effects. Cell 2014; 159: 318- 32.
|
157 |
Lynes MD , Leiria LO , Lundh M et al. The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat Med 2017; 23: 631- 7.
|
158 |
Zhou P , Santoro A , Peroni OD et al. PAHSAs enhance hepatic and systemic insulin sensitivity through direct and indirect mechanisms. J Clin Invest 2019; 129: 4138- 50.
|
159 |
Syed I , Lee J , Moraes-Vieira PM et al. Palmitic acid hydroxystearic acids activate GPR40, which is involved in their beneficial effects on glucose homeostasis. Cell Metab 2018; 27: 419- 27.e4.
|
160 |
Kuda O , Brezinova M , Rombaldova M et al. Docosahexaenoic acid-derived fatty acid esters of hydroxy fatty acids (FAHFAs) with anti-inflammatory properties. Diabetes 2016; 65: 2580- 90.
|
161 |
Hammarstedt A , Syed I , Vijayakumar A et al. Adipose tissue dysfunction is associated with low levels of the novel Palmitic Acid Hydroxystearic Acids. Sci Rep 2018; 8: 15757.
|
162 |
Patel R , Santoro A , Hofer P et al. ATGL is a biosynthetic enzyme for fatty acid esters of hydroxy fatty acids. Nature 2022; 606: 968- 75.
|
163 |
Syed I , Lee J , Peroni OD et al. Methodological issues in studying PAHSA biology: masking PAHSA effects. Cell Metab 2018; 28: 543- 6.
|
164 |
Pflimlin E , Bielohuby M , Korn M et al. Acute and repeated treatment with 5-PAHSA or 9-PAHSA isomers does not improve glucose control in mice. Cell Metab 2018; 28: 217- 27.e13.
|
165 |
Macêdo APA , Muñoz VR , Cintra DE et al. 12,13-diHOME as a new therapeutic target for metabolic diseases. Life Sci 2022; 290: 120229.
|
166 |
Stanford KI , Lynes MD , Takahashi H et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab 2018; 27: 1357.
|
167 |
Vasan SK , Noordam R , Gowri MS et al. The proposed systemic thermogenic metabolites succinate and 12,13-diHOME are inversely associated with adiposity and related metabolic traits: evidence from a large human cross-sectional study. Diabetologia 2019; 62: 2079- 87.
|
168 |
Pinckard KM , Shettigar VK , Wright KR et al. A novel endocrine role for the BAT-released lipokine 12,13-diHOME to mediate cardiac function. Circulation 2021; 143: 145- 59.
|
169 |
Leiria LO , Wang CH , Lynes MD et al. 12-lipoxygenase regulates cold adaptation and glucose metabolism by producing the omega-3 lipid 12-HEPE from brown fat. Cell Metab 2019; 30: 768- 83.e7.
|
170 |
Borea PA , Gessi S , Merighi S et al. Pharmacology of adenosine receptors: the state of the art. Physiol Rev 2018; 98: 1591- 625.
|
171 |
Zimmermann H , Zebisch M , Strater N . Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal 2012; 8: 437- 502.
|
172 |
Schimmel RJ , McCarthy L . Role of adenosine as an endogenous regulator of respiration in hamster brown adipocytes. Am J Physiol 1984; 246: C301- 7.
|
173 |
Gnad T , Scheibler S , von Kügelgen I et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 2014; 516: 395- 9.
|
174 |
Ding M , Ma YJ , Du RQ et al. CHCHD10 modulates thermogenesis of adipocytes by regulating lipolysis. Diabetes 2022; 71: 1862- 79.
|
175 |
Szillat D , Bukowiecki LJ . Control of brown adipose tissue lipolysis and respiration by adenosine. Am J Physiol 1983; 245: E555- 9.
|
176 |
Unelius L , Mohell N , Nedergaard J . Cold acclimation induces desensitization to adenosine in brown fat cells without changing receptor binding. Am J Physiol 1990; 258: C818- 26.
|
177 |
Woodward JA , Saggerson ED . Effect of adenosine deaminase, N6-phenylisopropyladenosine and hypothyroidism on the responsiveness of rat brown adipocytes to noradrenaline. Biochem J 1986; 238: 395- 403.
|
178 |
Niemann B , Haufs-Brusberg S , Puetz L et al. Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine. Nature 2022; 609: 361- 8.
|
179 |
Cocucci E , Meldolesi J . Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol 2015; 25: 364- 72.
|
180 |
Mori MA , Ludwig RG , Garcia-Martin R et al. Extracellular miRNAs: from biomarkers to mediators of physiology and disease. Cell Metab 2019; 30: 656- 73.
|
181 |
Garcia-Martin R , Wang G , Brandão BB et al. MicroRNA sequence codes for small extracellular vesicle release and cellular retention. Nature 2022; 601: 446- 51.
|
182 |
Thomou T , Mori MA , Dreyfuss JM et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 2017; 542: 450- 5.
|
183 |
Li D , Song H , Shuo L et al. Gonadal white adipose tissue-derived exosomal miR-222 promotes obesity-associated insulin resistance. Aging (Albany NY) 2020; 12: 22719- 43.
|
184 |
Yu Y , Du H , Wei S et al. Adipocyte-derived exosomal miR-27a induces insulin resistance in skeletal muscle through repression of PPARγ. Theranostics 2018; 8: 2171- 88.
|
185 |
Wang YC , Li Y , Wang XY et al. Circulating miR-130b mediates metabolic crosstalk between fat and muscle in overweight/obesity. Diabetologia 2013; 56: 2275- 85.
|
186 |
Tang Y , Yang LJ , Liu H et al. Exosomal miR-27b-3p secreted by visceral adipocytes contributes to endothelial inflammation and atherogenesis. Cell Rep 2023; 42: 111948.
|
187 |
Xu J , Cui L , Wang J et al. Cold-activated brown fat-derived extracellular vesicle-miR-378a-3p stimulates hepatic gluconeogenesis in male mice. Nat Commun 2023; 14: 5480.
|
188 |
Wang J , Li L , Zhang Z et al. Extracellular vesicles mediate the communication of adipose tissue with brain and promote cognitive impairment associated with insulin resistance. Cell Metab 2022; 34: 1264- 79.e8.
|
189 |
Pan Y , Hui X , Hoo RLC et al. Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation. J Clin Invest 2019; 129: 834- 49.
|
190 |
Zhang Y , Mei H , Chang X et al. Adipocyte-derived microvesicles from obese mice induce M1 macrophage phenotype through secreted miR-155. J Mol Cell Biol 2016; 8: 505- 17.
|
191 |
Zhao H , Shang Q , Pan Z et al. Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and Beiging in white adipose tissue. Diabetes 2018; 67: 235- 47.
|
192 |
Ying W , Riopel M , Bandyopadhyay G et al. Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell 2017; 171: 372- 84.e12.
|
193 |
Ying W , Gao H , Dos Reis FCG et al. miR-690, an exosomal-derived miRNA from M2-polarized macrophages, improves insulin sensitivity in obese mice. Cell Metab 2021; 33: 781- 90.e5.
|
194 |
Zhang Y , Yu M , Dong J et al. Identification of novel adipokines through proteomic profiling of small extracellular vesicles derived from adipose tissue. J Proteome Res 2020; 19: 3130- 42.
|
195 |
Lee JE , Moon PG , Lee IK et al. Proteomic analysis of extracellular vesicles released by adipocytes of otsuka long-evans tokushima fatty (OLETF) rats. Protein J 2015; 34: 220- 35.
|
196 |
Sano S , Izumi Y , Yamaguchi T et al. Lipid synthesis is promoted by hypoxic adipocyte-derived exosomes in 3T3-L1 cells. Biochem Biophys Res Commun 2014; 445: 327- 33.
|
197 |
Liu Z , Gan L , Zhang T et al. Melatonin alleviates adipose inflammation through elevating α-ketoglutarate and diverting adipose-derived exosomes to macrophages in mice. J Pineal Res 1245; 64: e12455.
|
198 |
Flaherty SE 3rd , Grijalva A , Xu X et al. A lipase-independent pathway of lipid release and immune modulation by adipocytes. Science 2019; 363: 989- 93.
|
199 |
Blandin A , Dugail I , Hilairet G et al. Lipidomic analysis of adipose-derived extracellular vesicles reveals specific EV lipid sorting informative of the obesity metabolic state. Cell Rep 2023; 42: 112169.
|
200 |
Liang W , Sagar S , Ravindran R et al. Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired. Nat Commun 2023; 14: 5031.
|
201 |
Crewe C , Funcke JB , Li S et al. Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes. Cell Metab 2021; 33: 1853- 68.e11.
|
202 |
Rosina M , Ceci V , Turchi R et al. Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue. Cell Metab 2022; 34: 533- 48.e12.
|
203 |
He Y , Rodrigues RM , Wang X et al. Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223-enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis. J Clin Invest 2021; 131: e141513.
|
204 |
Kahn D , Macias E , Zarini S et al. Exploring visceral and subcutaneous adipose tissue secretomes in human obesity: implications for metabolic disease. Endocrinology 2022; 163: bqac140.
|
205 |
Baruch A , Wong C , Chinn LW et al. Antibody-mediated activation of the FGFR1/Klothoβ complex corrects metabolic dysfunction and alters food preference in obese humans. Proc Natl Acad Sci U S A 2020; 117: 28992- 9000.
|
206 |
Oikonomou EK , Antoniades C . The role of adipose tissue in cardiovascular health and disease. Nat Rev Cardiol 2019; 16: 83- 99.
|
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