New advances of adiponectin in regulating obesity and related metabolic syndromes

Yanqi Han; Qianwen Sun; Wei Chen; Yue Gao; Jun Ye; Yanmin Chen; Tingting Wang; Lili Gao; Yuling Liu; Yanfang Yang

doi:10.1016/j.jpha.2023.12.003

Volume 14 Issue 5

May 2024

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Article Navigation > Journal of Pharmaceutical Analysis > 2024 > 14(5): 100913

Yanqi Han, Qianwen Sun, Wei Chen, Yue Gao, Jun Ye, Yanmin Chen, Tingting Wang, Lili Gao, Yuling Liu, Yanfang Yang. New advances of adiponectin in regulating obesity and related metabolic syndromes[J]. Journal of Pharmaceutical Analysis, 2024, 14(5): 100913. doi: 10.1016/j.jpha.2023.12.003

Citation:

Yanqi Han, Qianwen Sun, Wei Chen, Yue Gao, Jun Ye, Yanmin Chen, Tingting Wang, Lili Gao, Yuling Liu, Yanfang Yang. New advances of adiponectin in regulating obesity and related metabolic syndromes[J]. Journal of Pharmaceutical Analysis, 2024, 14(5): 100913. doi: 10.1016/j.jpha.2023.12.003

Citation:

Yanqi Han, Qianwen Sun, Wei Chen, Yue Gao, Jun Ye, Yanmin Chen, Tingting Wang, Lili Gao, Yuling Liu, Yanfang Yang. New advances of adiponectin in regulating obesity and related metabolic syndromes[J]. Journal of Pharmaceutical Analysis, 2024, 14(5): 100913. doi: 10.1016/j.jpha.2023.12.003

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New advances of adiponectin in regulating obesity and related metabolic syndromes

doi: 10.1016/j.jpha.2023.12.003

Yanqi Han^a,b,
Qianwen Sun^a,b,
Wei Chen^a,b,
Yue Gao^a,b,
Jun Ye^a,b,
Yanmin Chen^a,b,
Tingting Wang^a,b,
Lili Gao^a,b,
Yuling Liu^{a,b
,
,},
Yanfang Yang^{a,b
,
,}

a. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China;
b. Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China

Funds:

This work was supported by the grants from the CAMS Innovation Fund for Medical Sciences (CIFMS) (Grant No.: 2021-I2M-1-026) and the Beijing Natural Science Foundation of China (Grant Nos.: 7212155 and 7162135).

Received Date: Sep. 08, 2023
Accepted Date: Dec. 07, 2023
Rev Recd Date: Nov. 18, 2023
Publish Date: May 30, 2024

Abstract

Abstract

Obesity and related metabolic syndromes have been recognized as important disease risks, in which the role of adipokines cannot be ignored. Adiponectin (ADP) is one of the key adipokines with various beneficial effects, including improving glucose and lipid metabolism, enhancing insulin sensitivity, reducing oxidative stress and inflammation, promoting ceramides degradation, and stimulating adipose tissue vascularity. Based on those, it can serve as a positive regulator in many metabolic syndromes, such as type 2 diabetes (T2D), cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), sarcopenia, neurodegenerative diseases, and certain cancers. Therefore, a promising therapeutic approach for treating various metabolic diseases may involve elevating ADP levels or activating ADP receptors. The modulation of ADP genes, multimerization, and secretion covers the main processes of ADP generation, providing a comprehensive orientation for the development of more appropriate therapeutic strategies. In order to have a deeper understanding of ADP, this paper will provide an all-encompassing review of ADP.
- Adiponectin,
- Obesity,
- Metabolic syndrome,
- Regulation

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References(179)

References

[1]	K. Khoramipour, K. Chamari, A.A. Hekmatikar, et al., Adiponectin: Structure, physiological functions, role in diseases, and effects of nutrition, Nutrients 13 (2021), 1180.
[2]	H. Sun, P. Saeedi, S. Karuranga, et al., IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045, Diabetes Res. Clin. Pract. 183 (2022), 109119.
[3]	A.M. Allen, J.V. Lazarus, Z.M. Younossi, Healthcare and socioeconomic costs of NAFLD: A global framework to navigate the uncertainties, J. Hepatol. 79 (2023), 209-217.
[4]	R. Aggarwal, R.W. Yeh, K.E. Joynt Maddox, et al., Cardiovascular Risk Factor Prevalence, Treatment, and Control in US Adults Aged 20 to 44 Years, 2009 to March 2020, JAMA 329 (2023), 899-909.
[5]	A. Sarmento-Cabral, J.R. Peinado, L.C. Halliday, et al., Adipokines (leptin, adiponectin, resistin) differentially regulate all hormonal cell types in primary anterior pituitary cell cultures from two primate species, Sci. Rep. 7 (2017), 43537.
[6]	P.V. Dludla, B.B. Nkambule, S.E. Mazibuko-Mbeje, et al., Adipokines as a therapeutic target by metformin to improve metabolic function: A systematic review of randomized controlled trials, Pharmacol. Res. 163 (2021), 105219.
[7]	M. Esfahani, A. Movahedian, M. Baranchi, et al., Adiponectin: An adipokine with protective features against metabolic syndrome, Iran. J. Basic Med. Sci. 18 (2015) 430-442.
[8]	S.C. Shabalala, P.V. Dludla, L. Mabasa, et al., The effect of adiponectin in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and the potential role of polyphenols in the modulation of adiponectin signaling, Biomed. Pharmacother. 131 (2020), 110785.
[9]	M. Gao, D. Cui, J. Xie, The role of adiponectin for immune cell function in metabolic diseases, Diabetes Obes. Metab. 25 (2023) 2427-2438.
[10]	W. Han, S. Yang, H. Xiao, et al., Role of adiponectin in cardiovascular diseases related to glucose and lipid metabolism disorders, Int. J. Mol. Sci. 23 (2022), 15627.
[11]	P.E. Scherer, S. Williams, M. Fogliano, et al., A novel serum protein similar to C1q, produced exclusively in adipocytes, J. Biol. Chem. 270 (1995) 26746-26749.
[12]	P. Zahradka, C.G. Taylor, L. Tworek, et al., Thrombin-mediated Formation of globular adiponectin promotes an increase in adipose tissue mass, Biomolecules 13 (2022), 30.
[13]	J. Fruebis, T.S. Tsao, S. Javorschi, et al., Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice, Proc. Natl. Acad. Sci. USA 98 (2001) 2005-2010.
[14]	N. Halberg, T.D. Schraw, Z.V. Wang, et al., Systemic fate of the adipocyte-derived factor adiponectin, Diabetes 58 (2009) 1961-1970.
[15]	T. Yamauchi, Y. Nio, T. Maki, et al., Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions, Nat. Med. 13 (2007) 332-339.
[16]	B. Chaurasia, S.A. Summers, Ceramides in metabolism: Key lipotoxic players, Annu. Rev. Physiol. 83 (2021) 303-330.
[17]	M. Ruiz, R. Devkota, D. Panagaki, et al., Sphingosine 1-phosphate mediates adiponectin receptor signaling essential for lipid homeostasis and embryogenesis, Nat. Commun. 13 (2022), 7162.
[18]	R. Pascolutti, S.C. Erlandson, D.J. Burri, et al., Mapping and engineering the interaction between adiponectin and T-cadherin, J. Biol. Chem. 295 (2020) 2749-2759.
[19]	Y. Obata, S. Kita, Y. Koyama, et al., Adiponectin/T-cadherin system enhances exosome biogenesis and decreases cellular ceramides by exosomal release, JCI Insight 3 (2018), e99680.
[20]	A.H. Tsang, C.E. Koch, J.T. Kiehn, et al., An adipokine feedback regulating diurnal food intake rhythms in mice, Elife 9 (2020), e55388.
[21]	T. Wada, Y. Yamamoto, Y. Takasugi, et al., Adiponectin regulates the circadian rhythm of glucose and lipid metabolism, J. Endocrinol. 254 (2022) 121-133.
[22]	P. Singh, P. Sharma, K.R. Sahakyan, et al., Differential effects of leptin on adiponectin expression with weight gain versus obesity, Int. J. Obes. (Lond) 40 (2016) 266-274.
[23]	T. Hajri, H. Tao, J. Wattacheril, et al., Regulation of adiponectin production by insulin: Interactions with tumor necrosis factor-α and interleukin-6, Am. J. Physiol. Endocrinol. Metab. 300 (2011) E350-E360.
[24]	S.R. Farmer, Transcriptional control of adipocyte formation, Cell Metab. 4 (2006) 263-273.
[25]	S. Zhao, C.M. Kusminski, P.E. Scherer, Adiponectin, leptin and cardiovascular disorders, Circ. Res. 128 (2021) 136-149.
[26]	N. Hosogai, A. Fukuhara, K. Oshima, et al., Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation, Diabetes 56 (2007) 901-911.
[27]	S. Furukawa, T. Fujita, M. Shimabukuro, et al., Increased oxidative stress in obesity and its impact on metabolic syndrome, J. Clin. Invest. 114 (2004) 1752-1761.
[28]	J.T. Stadler, S. Lackner, S. Morkl, et al., Obesity affects HDL metabolism, composition and subclass distribution, Biomedicines 9 (2021), 242.
[29]	L. Perez, A. Vallejos, C. Echeverria, et al., OxHDL controls LOX-1 expression and plasma membrane localization through a mechanism dependent on NOX/ROS/NF-κB pathway on endothelial cells, Lab. Invest. 99 (2019) 421-437.
[30]	O.J. Rivera-Gonzalez, L. Coats, J.S. Speed, Abstract P158: Endothelin inhibits adiponectin production via ETB receptor activation on adipocytes, Hypertension 78 (2021): AP158.
[31]	M. Zocchi, M. Della Porta, F. Lombardoni, et al., A potential interplay between HDLs and adiponectin in promoting endothelial dysfunction in obesity, Biomedicines 10 (2022), 1344.
[32]	T.R. Aprahamian, Elevated adiponectin expression promotes adipose tissue vascularity under conditions of diet-induced obesity, Metabolism 62 (2013) 1730-1738.
[33]	K. Ohashi, J.L. Parker, N. Ouchi, et al., Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype, J. Biol. Chem. 285 (2010) 6153-6160.
[34]	S. Cinti, G. Mitchell, G. Barbatelli, et al., Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans, J. Lipid Res. 46 (2005) 2347-2355.
[35]	K. Sun, J. Tordjman, K. Clement, et al., Fibrosis and adipose tissue dysfunction, Cell Metab. 18 (2013) 470-477.
[36]	M. Iwaki, M. Matsuda, N. Maeda, et al., Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors, Diabetes 52 (2003) 1655-1663.
[37]	L. Qiang, L. Wang, N. Kon, et al., Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ, Cell 150 (2012) 620-632.
[38]	Y. He, A.B. Taub, L. Yu, et al., PPARγ acetylation orchestrates adipose plasticity and metabolic rhythms, Adv. Sci. 10 (2023), e2204190.
[39]	S.A. Yi, Y.J. Jeon, M.G. Lee, et al., S6K1 controls adiponectin expression by inducing a transcriptional switch: BMAL1-to-EZH2, Exp. Mol. Med. 54 (2022) 324-333.
[40]	S.A. Yi, S.H. Um, J. Lee, et al., S6K1 phosphorylation of H2B mediates EZH2 trimethylation of H3: A determinant of early adipogenesis, Mol. Cell 62 (2016) 443-452.
[41]	R. Fan, X. Peng, L. Xie, et al., Importance of Bmal1 in Alzheimer’s disease and associated aging-related diseases: Mechanisms and interventions, Aging Cell 21 (2022), e13704.
[42]	A.C. Doran, N. Meller, A. Cutchins, et al., The helix-loop-helix factors Id3 and E47 are novel regulators of adiponectin, Circ. Res. 103 (2008) 624-634.
[43]	L. Qiao, P.S. MacLean, J. Schaack, et al., C/EBPα regulates human adiponectin gene transcription through an intronic enhancer, Diabetes 54 (2005) 1744-1754.
[44]	L. Qiao, J. Shao, SIRT1 regulates adiponectin gene expression through Foxo1-C/enhancer-binding protein α transcriptional complex, J. Biol. Chem. 281 (2006) 39915-39924.
[45]	H.B. Kim, W.H. Kim, K.L. Han, et al., cAMP-response element binding protein (CREB) positively regulates mouse adiponectin gene expression in 3T3-L1 adipocytes, Biochem. Biophys. Res. Commun. 391 (2010) 634-639.
[46]	R. Natarajan, F.N. Salloum, B.J. Fisher, et al., Hypoxia inducible factor-1 upregulates adiponectin in diabetic mouse hearts and attenuates post-ischemic injury, J. Cardiovasc. Pharmacol. 51 (2008) 178-187.
[47]	T. Kobayashi, H. Imachi, K. Fukunaga, et al., HDL promotes adiponectin gene expression via the CAMKK/CAMKIV pathway, J. Mol. Endocrinol. 68 (2022) 89-98.
[48]	K. Hara, M. Horikoshi, T. Yamauchi, et al., Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome, Diabetes Care 29 (2006) 1357-1362.
[49]	Y. Wang, K.S.L. Lam, M.H. Yau, et al., Post-translational modifications of adiponectin: Mechanisms and functional implications, Biochem. J. 409 (2008) 623-633.
[50]	Y. Wang, A. Xu, C. Knight, et al., Hydroxylation and glycosylation of the four conserved lysine residues in the collagenous domain of adiponectin. Potential role in the modulation of its insulin-sensitizing activity, J. Biol. Chem. 277 (2002) 19521-19529.
[51]	A.A. Richards, T. Stephens, H.K. Charlton, et al., Adiponectin multimerization is dependent on conserved lysines in the collagenous domain: Evidence for regulation of multimerization by alterations in posttranslational modifications, Mol. Endocrinol. 20 (2006) 1673-1687.
[52]	M. Liu, L. Zhou, A. Xu, et al., A disulfide-bond A oxidoreductase-like protein (DsbA-L) regulates adiponectin multimerization, Proc. Natl. Acad. Sci. U. S. A. 105 (2008) 18302-18307.
[53]	Z.V. Wang, T.D. Schraw, J.Y. Kim, et al., Secretion of the adipocyte-specific secretory protein adiponectin critically depends on thiol-mediated protein retention, Mol. Cell. Biol. 27 (2007) 3716-3731.
[54]	H. Sha, L. Yang, M. Liu, et al., Adipocyte spliced form of X-box-binding protein 1 promotes adiponectin multimerization and systemic glucose homeostasis, Diabetes 63 (2014) 867-879.
[55]	S.C. Su, C.Y. Chien, Y. Chen, et al., PDIA4, a novel ER stress chaperone, modulates adiponectin expression and inflammation in adipose tissue, Biofactors 48 (2022) 1060-1075.
[56]	C. Brannmark, E.I. Kay, U. Ortegren Kugelberg, et al., Adiponectin is secreted via caveolin 1-dependent mechanisms in white adipocytes, J. Endocrinol. 247 (2020) 25-38.
[57]	C.H. Wang, C.C. Wang, H.C. Huang, et al., Mitochondrial dysfunction leads to impairment of insulin sensitivity and adiponectin secretion in adipocytes, FEBS J. 280 (2013) 1039-1050.
[58]	S. Weng, J.C. Wu, F.C. Shen, et al., Chaperonin counteracts diet-induced non-alcoholic fatty liver disease by aiding sirtuin 3 in the control of fatty acid oxidation, Diabetologia 66 (2023) 913-930.
[59]	F. Baldini, R. Fabbri, C. Eberhagen, et al., Adipocyte hypertrophy parallels alterations of mitochondrial status in a cell model for adipose tissue dysfunction in obesity, Life Sci. 265 (2021), 118812.
[60]	K. Kuramoto, Y.J. Kim, J.H. Hong, et al., The autophagy protein Becn1 improves insulin sensitivity by promoting adiponectin secretion via exocyst binding, Cell Rep. 35 (2021), 109184.
[61]	I.L.M.H. Aye, F.J. Rosario, A. Kramer, et al., Insulin increases adipose adiponectin in pregnancy by inhibiting ubiquitination and degradation: Impact of obesity, J. Clin. Endocrinol. Metab. 107 (2022) 53-66.
[62]	H. Makimura, T.M. Mizuno, H. Bergen, et al., Adiponectin is stimulated by adrenalectomy in ob/ob mice and is highly correlated with resistin mRNA, Am. J. Physiol. Endocrinol. Metab. 283 (2002) E1266-E1271.
[63]	Y. Benomar, H. Amine, D. Crepin, et al., Central resistin/TLR4 impairs adiponectin signaling, contributing to insulin and FGF21 resistance, Diabetes 65 (2016) 913-926.
[64]	Z. Lin, H. Tian, K.S.L. Lam, et al., Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice, Cell Metab. 17 (2013) 779-789.
[65]	W.L. Holland, A.C. Adams, J.T. Brozinick, et al., An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice, Cell Metab. 17 (2013) 790-797.
[66]	M.S. Han, R.J. Perry, J.P. Camporez, et al., A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21, Genes Dev. 35 (2021) 133-146.
[67]	M. Chikamatsu, H. Watanabe, Y. Shintani, et al., Albumin-fused long-acting FGF21 analogue for the treatment of non-alcoholic fatty liver disease, J. Controlled Release 355 (2023) 42-53.
[68]	M. Fasshauer, S. Kralisch, M. Klier, et al., Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes, Biochem. Biophys. Res. Commun. 301 (2003) 1045-1050.
[69]	K. Kim, J.K. Kang, Y.H. Jung, et al., Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver, Nat. Commun. 12 (2021), 1822.
[70]	L. Qiang, H. Wang, S.R. Farmer, Adiponectin secretion is regulated by SIRT1 and the endoplasmic reticulum oxidoreductase Ero1-L α, Mol. Cell. Biol. 27 (2007) 4698-4707.
[71]	M.F. El Hachmane, A.M. Komai, C.S. Olofsson, Cooling reduces cAMP-stimulated exocytosis and adiponectin secretion at a Ca²⁺-dependent step in 3T3-L1 adipocytes, PLoS One 10 (2015), e0119530.
[72]	A.M. Komai, C. Brannmark, S. Musovic, et al., PKA-independent cAMP stimulation of white adipocyte exocytosis and adipokine secretion: Modulations by Ca²⁺ and ATP, J. Physiol. 592 (2014) 5169-5186.
[73]	C. Christopher, D.W. Kang, A. Normann, et al., Impact of circuit, interval-based exercise on insulin resistance and adiponectin among minority cancer survivors, J. Clin. Oncol. 40 (2022), 12059.
[74]	J.M. Rutkowski, N. Halberg, Q. Wang, et al., Differential transendothelial transport of adiponectin complexes, Cardiovasc. Diabetol. 13 (2014), 47.
[75]	N. Yoon, K. Dadson, T. Dang, et al., Tracking adiponectin biodistribution via fluorescence molecular tomography indicates increased vascular permeability after streptozotocin-induced diabetes, Am. J. Physiol. Endocrinol. Metab. 317 (2019) E760-E772.
[76]	T.Q. Dang, N. Yoon, H. Chasiotis, et al., Transendothelial movement of adiponectin is restricted by glucocorticoids, J. Endocrinol. 234 (2017) 101-114.
[77]	D. Koutaki, A. Michos, F. Bacopoulou, et al., The emerging role of Sfrp5 and Wnt5a in the pathogenesis of obesity: Implications for a healthy diet and lifestyle, Nutrients 13 (2021), 2459.
[78]	M. Rydzewska, A. Nikolajuk, N. Matulewicz, et al., Serum secreted frizzled-related protein 5 in relation to insulin sensitivity and its regulation by insulin and free fatty acids, Endocrine 74 (2021) 300-307.
[79]	H.N. Jung, C.H. Jung, The role of anti-inflammatory adipokines in cardiometabolic disorders: Moving beyond adiponectin, Int. J. Mol. Sci. 22 (2021), 13529.
[80]	Y. Duan, S. Zhang, Y. Xing, et al., Adiponectin-mediated promotion of CD44 suppresses diabetic vascular inflammatory effects, iScience 26 (2023), 106428.
[81]	T. Onodera, D.S. Kim, R. Ye, et al., Protective roles of adiponectin and molecular signatures of HNF4α and PPARα as downstream targets of adiponectin in pancreatic β cells, Mol. Metab. 78 (2023), 101821.
[82]	K.G.M.M. Alberti, R.H. Eckel, S.M. Grundy, et al., Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity, Circulation 120 (2009) 1640-1645.
[83]	J.Y. Kim, E. van de Wall, M. Laplante, et al., Obesity-associated improvements in metabolic profile through expansion of adipose tissue, J. Clin. Invest. 117 (2007) 2621-2637.
[84]	I.W. Asterholm, P.E. Scherer, Enhanced metabolic flexibility associated with elevated adiponectin levels, Am. J. Pathol. 176 (2010) 1364-1376.
[85]	X. Li, D. Zhang, D.F. Vatner, et al., Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice, Proc. Natl. Acad. Sci. USA 117 (2020) 32584-32593.
[86]	S. Jeerawattanawart, P. Siripurkpong, S. Roytrakul, et al., IL-25 directly modulates adipocyte function and inflammation through the regulation of adiponectin, Inflamm. Res. 71 (2022) 1229-1244.
[87]	H. Xu, Q. Zhao, N. Song, et al., AdipoR1/AdipoR2 dual agonist recovers nonalcoholic steatohepatitis and related fibrosis via endoplasmic reticulum-mitochondria axis, Nat. Commun. 11 (2020), 5807.
[88]	Y.H. Jeon, M. He, J. Austin, et al., Adiponectin enhances the bioenergetics of cardiac myocytes via an AMPK- and succinate dehydrogenase-dependent mechanism, Cell. Signal. 78 (2021), 109866.
[89]	J.J. Ye, X. Bian, J. Lim, et al., Adiponectin and related C1q/TNF-related proteins bind selectively to anionic phospholipids and sphingolipids, Proc. Natl. Acad. Sci. USA 117 (2020) 17381-17388.
[90]	V. Rotter, I. Nagaev, U. Smith, Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects, J. Biol. Chem. 278 (2003) 45777-45784.
[91]	H. Sell, M. Bluher, N. Kloting, et al., Adipose dipeptidyl peptidase-4 and obesity: Correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro, Diabetes Care 36 (2013) 4083-4090.
[92]	T. Kadowaki, T. Yamauchi, Adiponectin and adiponectin receptors, Endocr. Rev. 26 (2005) 439-451.
[93]	T.P. Combs, U.B. Pajvani, A.H. Berg, et al., A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity, Endocrinology 145 (2004) 367-383.
[94]	M. Awazawa, K. Ueki, K. Inabe, et al., Adiponectin enhances insulin sensitivity by increasing hepatic IRS-2 expression via a macrophage-derived IL-6-dependent pathway, Cell Metab. 13 (2011) 401-412.
[95]	A.C. Munhoz, J.D.C. Serna, E.A. Vilas-Boas, et al., Adiponectin reverses β-Cell damage and impaired insulin secretion induced by obesity, Aging Cell 22 (2023), e13827.
[96]	M. Abou-Samra, C.M. Selvais, N. Dubuisson, et al., Adiponectin and its mimics on skeletal muscle: Insulin sensitizers, fat burners, exercise mimickers, muscling pills … or everything together? Int. J. Mol. Sci. 21 (2020), 2620.
[97]	T. Gamberi, A. Modesti, F. Magherini, et al., Activation of autophagy by globular adiponectin is required for muscle differentiation, Biochim. Biophys. Acta 1863 (2016) 694-702.
[98]	K. Komici, A. Dello Iacono, A. De Luca, et al., Adiponectin and sarcopenia: A systematic review with meta-analysis, Front. Endocrinol. 12 (2021), 576619.
[99]	L.B. Verdijk, T. Snijders, M. Drost, et al., Satellite cells in human skeletal muscle; from birth to old age, Age (Dordr) 36 (2014) 545-547.
[100]	G. Morozzi, S. Beccafico, R. Bianchi, et al., Oxidative stress-induced S100B accumulation converts myoblasts into brown adipocytes via an NF-κB/YY1/miR-133 axis and NF-κB/YY1/BMP-7 axis, Cell Death Differ. 24 (2017) 2077-2088.
[101]	Y. Tanaka, S. Kita, H. Nishizawa, et al., Adiponectin promotes muscle regeneration through binding to T-cadherin, Sci. Rep. 9 (2019), 16.
[102]	P. Fang, Y. She, M. Yu, et al., Adipose-Muscle crosstalk in age-related metabolic disorders: The emerging roles of adipo-myokines, Ageing Res. Rev. 84 (2023), 101829.
[103]	K.K.Y. Cheng, K.S.L. Lam, Y. Wang, et al., Adiponectin-induced endothelial nitric oxide synthase activation and nitric oxide production are mediated by APPL1 in endothelial cells, Diabetes 56 (2007) 1387-1394.
[104]	C. Farah, L.Y.M. Michel, J.L. Balligand, Nitric oxide signalling in cardiovascular health and disease, Nat. Rev. Cardiol. 15 (2018) 292-316.
[105]	W. Zhang, C. Shu, Q. Li, et al., Adiponectin affects vascular smooth muscle cell proliferation and apoptosis through modulation of the mitofusin-2-mediated Ras-Raf-Erk1/2 signaling pathway, Mol. Med. Rep. 12 (2015) 4703-4707.
[106]	R. Guo, M. Han, J. Song, et al., Adiponectin and its receptors are involved in hypertensive vascular injury, Mol. Med. Rep. 17 (2018) 209-215.
[107]	W. Nour-Eldine, C.M. Ghantous, K. Zibara, et al., Adiponectin attenuates angiotensin II-induced vascular smooth muscle cell remodeling through nitric oxide and the RhoA/ROCK pathway, Front. Pharmacol. 7 (2016), 86.
[108]	R. Shibata, K. Sato, D.R. Pimentel, et al., Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms, Nat. Med. 11 (2005) 1096-1103.
[109]	Y. Ikeda, K. Ohashi, R. Shibata, et al., Cyclooxygenase-2 induction by adiponectin is regulated by a sphingosine kinase-1 dependent mechanism in cardiac myocytes, FEBS Lett. 582 (2008) 1147-1150.
[110]	X. Lei, Q. Wu, W. Leng, et al., Exenatide reduces cardiomyocyte apoptosis by stimulating adiponectin secretion and activating APPL1-AMPK-PPARα axis, Ann. Transl. Med. 7 (2019), 326.
[111]	Y. Kim, J.H. Lim, E.N. Kim, et al., Adiponectin receptor agonist ameliorates cardiac lipotoxicity via enhancing ceramide metabolism in type 2 diabetic mice, Cell Death Dis. 13 (2022), 282.
[112]	Z. Zhou, C. Liu, S. Xu, et al., Metabolism regulator adiponectin prevents cardiac remodeling and ventricular arrhythmias via sympathetic modulation in a myocardial infarction model, Basic Res. Cardiol. 117 (2022), 34.
[113]	T. Gamberi, F. Magherini, A. Modesti, et al., Adiponectin signaling pathways in liver diseases, Biomedicines 6 (2018), 52.
[114]	X. Zhang, S. Yang, J. Chen, et al., Unraveling the regulation of hepatic gluconeogenesis, Front. Endocrinol. 9 (2019), 802.
[115]	J.M. Lee, W.Y. Seo, K.H. Song, et al., AMPK-dependent repression of hepatic gluconeogenesis via disruption of CREB.CRTC2 complex by orphan nuclear receptor small heterodimer partner, J. Biol. Chem. 285 (2010) 32182-32191.
[116]	R.A. Miller, Q. Chu, J. Le Lay, et al., Adiponectin suppresses gluconeogenic gene expression in mouse hepatocytes independent of LKB1-AMPK signaling, J. Clin. Invest. 121 (2011) 2518-2528.
[117]	J.H. Stern, J.M. Rutkowski, P.E. Scherer, Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk, Cell Metab. 23 (2016) 770-784.
[118]	J. Ryu, J.T. Hadley, Z. Li, et al., Adiponectin alleviates diet-induced inflammation in the liver by suppressing MCP-1 expression and macrophage infiltration, Diabetes 70 (2021) 1303-1316.
[119]	W.L. Holland, J.Y. Xia, J.A. Johnson, et al., Inducible overexpression of adiponectin receptors highlight the roles of adiponectin-induced ceramidase signaling in lipid and glucose homeostasis, Mol. Metab. 6 (2017) 267-275.
[120]	Y. Wang, X. Zhang, J. Shao, et al., Adiponectin regulates BMSC osteogenic differentiation and osteogenesis through the Wnt/β-catenin pathway, Sci. Rep. 7 (2017), 3652.
[121]	Y. Kim, C.W. Park, Mechanisms of adiponectin action: Implication of adiponectin receptor agonism in diabetic kidney disease, Int. J. Mol. Sci. 20 (2019), 1782.
[122]	S. Esmaeili, M. Motamedrad, M. Hemmati, et al., Prevention of kidney cell damage in hyperglycaemia condition by adiponectin, Cell Biochem. Funct. 37 (2019) 148-152.
[123]	M.Z.U.H. Shah, V.K. Shrivastava, S. Sofi, et al., Chlorogenic acid restores ovarian functions in mice with letrozole-induced polycystic ovarian syndrome via modulation of adiponectin receptor, Biomedicines 11 (2023), 900.
[124]	T.H. Lee, Ahadullah, B.R. Christie, et al., Chronic AdipoRon treatment mimics the effects of physical exercise on restoring hippocampal neuroplasticity in diabetic mice, Mol. Neurobiol. 58 (2021) 4666-4681.
[125]	S.Y. Yau, A. Li, R.L. Hoo, et al., Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin, Proc. Natl. Acad. Sci. USA 111 (2014) 15810-15815.
[126]	D.A. Formolo, T.H. Lee, J. Yu, et al., Increasing adiponectin signaling by sub-chronic AdipoRon treatment elicits antidepressant- and anxiolytic-like effects independent of changes in hippocampal plasticity, Biomedicines 11 (2023), 249.
[127]	N. Li, S. Zhao, Z. Zhang, et al., Adiponectin preserves metabolic fitness during aging, Elife 10 (2021), e65108.
[128]	K. He, L. Nie, T. Ali, et al., Adiponectin deficiency accelerates brain aging via mitochondria-associated neuroinflammation, Immun. Ageing 20 (2023), 15.
[129]	Y. Chen, J. Tao, P. Zhao, et al., Adiponectin receptor PAQR-2 signaling senses low temperature to promote C. elegans longevity by regulating autophagy, Nat. Commun. 10 (2019), 2602.
[130]	Y. Chen, Y. Ma, J. Tang, et al., Physical exercise attenuates age-related muscle atrophy and exhibits anti-ageing effects via the adiponectin receptor 1 signalling, J. Cachexia Sarcopenia Muscle 14 (2023), 1789-1801.
[131]	G.D. Naimo, L. Gelsomino, S. Catalano, et al., Interfering role of ERα on adiponectin action in breast cancer, Front. Endocrinol. 11 (2020), 66.
[132]	G.S. Christodoulatos, N. Spyrou, J. Kadillari, et al., The role of adipokines in breast cancer: Current evidence and perspectives, Curr. Obes. Rep. 8 (2019) 413-433.
[133]	S. Ando, G.D. Naimo, L. Gelsomino, et al., Novel insights into adiponectin action in breast cancer: Evidence of its mechanistic effects mediated by ERα expression, Obes. Rev. 21 (2020), e13004.
[134]	D. Chakraborty, W. Jin, J. Wang, The bifurcated role of adiponectin in colorectal cancer, Life Sci. 278 (2021), 119524.
[135]	Z. Zhang, J. Du, Q. Xu, et al., Adiponectin suppresses metastasis of nasopharyngeal carcinoma through blocking the activation of NF-κB and STAT3 signaling, Int. J. Mol. Sci. 23 (2022), 12729.
[136]	Y. Yan, H. Shi, Z. Zhao, et al., Adiponectin deficiency promotes endometrial carcinoma pathogenesis and development via activation of mitogen-activated protein kinase, J. Pathol. 257 (2022) 146-157.
[137]	A.Y. Jang, P.E. Scherer, J.Y. Kim, et al., Adiponectin and cardiometabolic trait and mortality: Where do we go? Cardiovasc. Res. 118 (2022) 2074-2084.
[138]	F. Tacke, T. Wustefeld, R. Horn, et al., High adiponectin in chronic liver disease and cholestasis suggests biliary route of adiponectin excretion in vivo, J. Hepatol. 42 (2005) 666-673.
[139]	A.B. Siegel, A. Goyal, M. Salomao, et al., Serum adiponectin is associated with worsened overall survival in a prospective cohort of hepatocellular carcinoma patients, Oncology 88 (2015) 57-68.
[140]	J. Shen, C.C. Yeh, Q. Wang, et al., Plasma adiponectin and hepatocellular carcinoma survival among patients without liver transplantation, Anticancer Res. 36 (2016) 5307-5314.
[141]	N.A. Sadik, A. Ahmed, S. Ahmed, The significance of serum levels of adiponectin, leptin, and hyaluronic acid in hepatocellular carcinoma of cirrhotic and noncirrhotic patients, Hum. Exp. Toxicol. 31 (2012) 311-321.
[142]	L.P. Bechmann, P. Kocabayoglu, J.P. Sowa, et al., Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis, Hepatology 57 (2013) 1394-1406.
[143]	R.S. Khan, T.S. Kato, A. Chokshi, et al., Adipose tissue inflammation and adiponectin resistance in patients with advanced heart failure: Correction after ventricular assist device implantation, Circ. Heart Fail. 5 (2012) 340-348.
[144]	K. Matsuda, Y. Fujishima, N. Maeda, et al., Positive feedback regulation between adiponectin and T-cadherin impacts adiponectin levels in tissue and plasma of male mice, Endocrinology 156 (2015) 934-946.
[145]	H.O. Kalkman, An explanation for the adiponectin paradox, Pharmaceuticals 14 (2021), 1266.
[146]	C. Menzaghi, V. Trischitta, The adiponectin paradox for all-cause and cardiovascular mortality, Diabetes 67 (2018) 12-22.
[147]	M. Matsuda, M. Suzuki, Y. Ajiro, et al., Involvement of growth differentiation factor 15 in paradoxical relationship between body mass index and mortality in patients with suspected or known coronary artery disease; The ANOX Study, Eur. Heart J. 43 (2022): ehac544.2391.
[148]	J. Bassols, J.M. Martinez-Calcerrada, I. Osiniri, et al., Effects of metformin administration on endocrine-metabolic parameters, visceral adiposity and cardiovascular risk factors in children with obesity and risk markers for metabolic syndrome: A pilot study, PLoS One 14 (2019), e0226303.
[149]	A. Tsuchida, T. Yamauchi, S. Takekawa, et al., Peroxisome proliferator-activated receptor (PPAR)alpha activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: Comparison of activation of PPARalpha, PPARgamma, and their combination, Diabetes 54 (2005) 3358-3370.
[150]	D. Ryan, A. Acosta, GLP-1 receptor agonists: Nonglycemic clinical effects in weight loss and beyond, Obesity (Silver Spring) 23 (2015) 1119-1129.
[151]	L. Zhang, M. Yang, H. Ren, et al., GLP-1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c-JNK, Liver Int. 33 (2013) 794-804.
[152]	A. Cahn, S. Cernea, I. Raz, An update on DPP-4 inhibitors in the management of type 2 diabetes, Expert Opin. Emerg. Drugs 21 (2016) 409-419.
[153]	T. Hibuse, N. Maeda, K. Kishida, et al., A pilot three-month sitagliptin treatment increases serum adiponectin level in Japanese patients with type 2 diabetes mellitus: A randomized controlled trial START-J study, Cardiovasc. Diabetol. 13 (2014), 96.
[154]	S.Y. Park, H.K. Shin, J.H. Lee, et al., Cilostazol ameliorates metabolic abnormalities with suppression of proinflammatory markers in a db/db mouse model of type 2 diabetes via activation of peroxisome proliferator-activated receptor gamma transcription, J. Pharmacol. Exp. Ther. 329 (2009) 571-579.
[155]	S.Y. Tseng, H.Y. Chang, Y. Li, et al., Effects of cilostazol on angiogenesis in diabetes through adiponectin/adiponectin receptors/Sirtuin1 signaling pathway, Int. J. Mol. Sci. 23 (2022), 14839.
[156]	R. Clasen, M. Schupp, A. Foryst-Ludwig, et al., PPARgamma-activating angiotensin type-1 receptor blockers induce adiponectin, Hypertension 46 (2005) 137-143.
[157]	F. Borghi, B. Seva-Pessoa, D.M. Grassi-Kassisse, The adipose tissue and the involvement of the renin-angiotensin-aldosterone system in cardiometabolic syndrome, Cell Tissue Res. 366 (2016) 543-548.
[158]	A. Sahebkar, G.F. Watts, Fibrate therapy and circulating adiponectin concentrations: A systematic review and meta-analysis of randomized placebo-controlled trials, Atherosclerosis 230 (2013) 110-120.
[159]	H.L. Jen, W.H. Yin, J.W. Chen, et al., Endothelin-1-induced cell hypertrophy in cardiomyocytes is improved by fenofibrate: Possible roles of adiponectin, J. Atheroscler. Thromb. 24 (2017) 508-517.
[160]	K. Oki, J. Koide, S. Nakanishi, et al., Fenofibrate increases high molecular weight adiponectin in subjects with hypertriglyceridemia, Endocr. J. 54 (2007) 431-435.
[161]	M. Valero-Munoz, B. Martin-Fernandez, S. Ballesteros, et al., Rosuvastatina mejora la sensibilidad a la insulina en ratas con sobrepeso inducido por dieta grasa. Papel de sirtuina 1 en el tejido adiposo, Clinica E Investig. En Arterioscler. 26 (2014) 161-167.
[162]	T. Tsutamoto, M. Yamaji, C. Kawahara, et al., Effect of simvastatin vs. rosuvastatin on adiponectin and haemoglobin A1c levels in patients with non-ischaemic chronic heart failure, Eur. J. Heart Fail. 11 (2009) 1195-1201.
[163]	D.N. Obanda, P. Zhao, A.J. Richard, et al., Stinging nettle (Urtica dioica L.) attenuates FFA induced ceramide accumulation in 3T3-L1 adipocytes in an adiponectin dependent manner, PLoS One 11 (2016), e0150252.
[164]	A. Hosseini, B.M. Razavi, M. Banach, et al., Quercetin and metabolic syndrome: A review, Phytother. Res. 35 (2021) 5352-5364.
[165]	H.N. Choi, S.M. Jeong, G.H. Huh, et al., Quercetin ameliorates insulin sensitivity and liver steatosis partly by increasing adiponectin expression in ob/ob mice, Food Sci. Biotechnol. 24 (2015) 273-279.
[166]	S. Wein, N. Behm, R.K. Petersen, et al., Quercetin enhances adiponectin secretion by a PPAR-gamma independent mechanism, Eur. J. Pharm. Sci. 41 (2010) 16-22.
[167]	F. Cheng, L. Han, Y. Xiao, et al., D- chiro-Inositol ameliorates high fat diet-induced hepatic steatosis and insulin resistance via PKCε-PI3K/AKT pathway, J. Agric. Food Chem. 67 (2019) 5957-5967.
[168]	Q. Yang, Y. Zhang, L. Li, et al., D- chiro-Inositol facilitates adiponectin biosynthesis and activates the AMPKα/PPARs pathway to inhibit high-fat diet-induced obesity and liver lipid deposition, Food Funct. 13 (2022) 7192-7203.
[169]	C. Ma, Z. Wang, R. Xia, et al., Danthron ameliorates obesity and MAFLD through activating the interplay between PPARα/RXRα heterodimer and adiponectin receptor 2, Biomed. Pharmacother. 137 (2021), 111344.
[170]	Y. Chen, C. Lian, Q. Sun, et al., Ramulus mori (Sangzhi) alkaloids alleviate high-fat diet-induced obesity and nonalcoholic fatty liver disease in mice, Antioxidants (Basel) 11 (2022), 905.
[171]	Q. Sun, C. Lian, Y. Chen, et al., Ramulus Mori (Sangzhi) alkaloids ameliorate obesity-linked adipose tissue metabolism and inflammation in mice, Nutrients 14 (2022), 5050.
[172]	Z. Wang, Z. Chen, F. Fang, et al., The role of adiponectin in periodontitis: Current state and future prospects, Biomed. Pharmacother. 137 (2021), 111358.
[173]	W. Gu, Y. Li, The therapeutic potential of the adiponectin pathway, BioDrugs 26 (2012) 1-8.
[174]	R. Nehme, M. Diab-Assaf, C. Decombat, et al., Targeting adiponectin in breast cancer, Biomedicines 10 (2022), 2958.
[175]	O.L. Jr, Potential adiponectin receptor response modifier therapeutics, Front. Endocrinol. 10 (2019), 539.
[176]	W. Qiu, H. Wu, Z. Hu, et al., Identification and characterization of a novel adiponectin receptor agonist adipo anti-inflammation agonist and its anti-inflammatory effects in vitro and in vivo, Br. J. Pharmacol. 178 (2021) 280-297.
[177]	W. Qiu, Z. Wang, Z. Chen, et al., The adiponectin receptor agonist AdipoAI attenuates periodontitis in diabetic rats by inhibiting gingival fibroblast-induced macrophage migration, Br. J. Pharmacol. 180 (2023) 2436-2451.
[178]	X. Zhou, Z. Cheng, M. Lu, et al., Adiponectin receptor agonist AdipoRon modulates human and mouse platelet function, Acta Pharmacol. Sin. 44 (2023) 356-366.
[179]	H. Wu, Y. Zhang, Y. Li, et al., Chemical synthesis and biological evaluations of adiponectin collagenous domain glycoforms, J. Am. Chem. Soc. 143 (2021) 7808-7818.