Therapeutic targeting of white adipose tissue metabolic dysfunction in obesity: mechanisms and opportunities

Abstract

White adipose tissue is not only a highly heterogeneous organ containing various cells, such as adipocytes, adipose stem and progenitor cells, and immune cells, but also an endocrine organ that is highly important for regulating metabolic and immune homeostasis. In individuals with obesity, dynamic cellular changes in adipose tissue result in phenotypic switching and adipose tissue dysfunction, including pathological expansion, WAT fibrosis, immune cell infiltration, endoplasmic reticulum stress, and ectopic lipid accumulation, ultimately leading to chronic low-grade inflammation and insulin resistance. Recently, many distinct subpopulations of adipose tissue have been identified, providing new insights into the potential mechanisms of adipose dysfunction in individuals with obesity. Therefore, targeting white adipose tissue as a therapeutic agent for treating obesity and obesity-related metabolic diseases is of great scientific interest. Here, we provide an overview of white adipose tissue remodeling in individuals with obesity including cellular changes and discuss the underlying regulatory mechanisms of white adipose tissue metabolic dysfunction. Currently, various studies have uncovered promising targets and strategies for obesity treatment. We also outline the potential therapeutic signaling pathways of targeting adipose tissue and summarize existing therapeutic strategies for antiobesity treatment including pharmacological approaches, lifestyle interventions, and novel therapies.

Keywords

adipose tissue remodeling / immunometabolic dysfunction / obesity / signaling pathways / therapeutic potentials

References

1	World Health Organization. Obesity and overweight. Accessed 1 March 2024, 2024.
2	Y Wang, L Zhao, L Gao, A Pan, H Xue. Health policy and public health implications of obesity in China. Lancet Diab Endocrinol. 2021;9(7):446-461.
3	YC Chooi, C Ding, F Magkos. The epidemiology of obesity. Metabolism. 2019;92:6-10.
4	CL Hoyt, JL Burnette, L Auster-Gussman. “Obesity is a disease”: examining the self-regulatory impact of this public-health message. Psychol Sci. 2014;25(4):997-1002.
5	A Afshin, MH Forouzanfar, MB Reitsma, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017;377(1):13-27.
6	N Stefan, AL Birkenfeld, MB Schulze. Global pandemics interconnected—obesity, impaired metabolic health and COVID-19. Nat Rev Endocrinol. 2021;17(3):135-149.
7	MW Schwartz, RJ Seeley, LM Zeltser, et al. Obesity pathogenesis: an endocrine society scientific statement. Endocr Rev. 2017;38(4):267-296.
8	M Hopkins, JE Blundell. Energy balance, body composition, sedentariness and appetite regulation: pathways to obesity. Clin Sci (Lond). 2016;130(18):1615-1628.
9	B Maniyadath, Q Zhang, RK Gupta, S Mandrup. Adipose tissue at single-cell resolution. Cell Metab. 2023;35(3):386-413.
10	ED Rosen, BM Spiegelman. What we talk about when we talk about fat. Cell. 2014;156(1):20-44.
11	EE Kershaw, JS Flier. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89(6):2548-2556.
12	M Adamczak, A Wiecek. The adipose tissue as an endocrine organ. Semin Nephrol. 2013;33(1):2-13.
13	Z Liu, KKL Wu, X Jiang, A Xu, KKY Cheng. The role of adipose tissue senescence in obesity- and ageing-related metabolic disorders. Clin Sci (Lond). 2020;134(2):315-330.
14	HS Schipper, B Prakken, E Kalkhoven, M Boes. Adipose tissue-resident immune cells: key players in immunometabolism. Trends Endocrinol Metab. 2012;23(8):407-415.
15	E Stolarczyk. Adipose tissue inflammation in obesity: a metabolic or immune response? Curr Opin Pharmacol. 2017;37:35-40.
16	M Itoh, T Suganami, R Hachiya, Y Ogawa. Adipose tissue remodeling as homeostatic inflammation. Int J Inflam. 2011;2011:720926.
17	S Virtue, A Vidal-Puig. Adipose tissue expandability, lipotoxicity and the metabolic syndrome — an allostatic perspective. Biochim Biophys Acta. 2010;1801(3):338-349.
18	M Koenen, MA Hill, P Cohen, JR Sowers. Obesity, adipose tissue and vascular dysfunction. Circ Res. 2021;128(7):951-968.
19	T McLaughlin, C Lamendola, A Liu, F Abbasi. Preferential fat deposition in subcutaneous versus visceral depots is associated with insulin sensitivity. J Clin Endocrinol Metab. 2011;96(11):E1756-E1760.
20	K Indulekha, RM Anjana, J Surendar, V Mohan. Association of visceral and subcutaneous fat with glucose intolerance, insulin resistance, adipocytokines and inflammatory markers in Asian Indians (CURES-113). Clin Biochem. 2011;44(4):281-287.
21	K Sun, CM Kusminski, PE Scherer. Adipose tissue remodeling and obesity. J Clin Invest. 2011;121(6):2094-2101.
22	T Kawai, MV Autieri, R Scalia. Adipose tissue inflammation and metabolic dysfunction in obesity. Am J Physiol Cell Physiol. 2021;320(3):C375-C391.
23	S Khan, YT Chan, XS Revelo, DA Winer. The immune landscape of visceral adipose tissue during obesity and aging. Front Endocrinol (Lausanne). 2020;11:267.
24	B Ahmed, R Sultana, MW Greene. Adipose tissue and insulin resistance in obese. Biomed Pharmacother. 2021;137:111315.
25	RL Smith, MR Soeters, RCI Wüst, RH Houtkooper. Metabolic flexibility as an adaptation to energy resources and requirements in health and disease. Endocr Rev. 2018;39(4):489-517.
26	DE Kelley, B Goodpaster, RR Wing, JA Simoneau. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Physiol. 1999;277(6):E1130-E1141.
27	DE Kelley, LJ Mandarino. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes. 2000;49(5):677-683.
28	A Bergouignan, E Antoun, I Momken, et al. Effect of contrasted levels of habitual physical activity on metabolic flexibility. J Appl Physiol (1985). 2013;114(3):371-379.
29	BH Goodpaster, LM Sparks. Metabolic flexibility in health and disease. Cell Metab. 2017;25(5):1027-1036.
30	LM Perez, H Pareja-Galeano, F Sanchis-Gomar, E Emanuele, A Lucia, BG Galvez. ‘Adipaging’: ageing and obesity share biological hallmarks related to a dysfunctional adipose tissue. J Physiol. 2016;594(12):3187-3207.
31	CW Chia, JM Egan, L Ferrucci. Age-related changes in glucose metabolism, hyperglycemia, and cardiovascular risk. Circ Res. 2018;123(7):886-904.
32	D Frasca, BB Blomberg, R Paganelli. Aging, obesity, and inflammatory age-related diseases. Front Immunol. 2017;8:1745.
33	MM Rosenkilde. Advances in incretin-based therapeutics for obesity. Nat Rev Endocrinol. 2024;20(2):67-68.
34	AM Jastreboff, LM Kaplan, JP Frías, et al. Triple-hormone-receptor agonist retatrutide for obesity—a phase 2 trial. N Engl J Med. 2023;389(6):514-526.
35	M Esteve Ràfols. Adipose tissue: cell heterogeneity and functional diversity. Endocrinol Nutr. 2014;61(2):100-112.
36	M Konige, H Wang, C Sztalryd. Role of adipose specific lipid droplet proteins in maintaining whole body energy homeostasis. Biochim Biophys Acta. 2014;1842(3):393-401.
37	M Longo, F Zatterale, J Naderi, et al. Adipose tissue dysfunction as determinant of obesity-associated metabolic complications. Int J Mol Sci. 2019;20(9):2358.
38	SS Choe, JY Huh, IJ Hwang, JI Kim, JB Kim. Adipose tissue remodeling: its role in energy metabolism and metabolic disorders. Front Endocrinol. 2016;7:30. Review.
39	F Liu, J He, H Wang, D Zhu, Y Bi. Adipose morphology: a critical factor in regulation of human metabolic diseases and adipose tissue dysfunction. Obes Surg. 2020;30(12):5086-5100.
40	E Maury, L No?l, R Detry, SM Brichard. In vitro hyperresponsiveness to tumor necrosis factor-alpha contributes to adipokine dysregulation in omental adipocytes of obese subjects. J Clin Endocrinol Metab. 2009;94(4):1393-1400.
41	A Michaud, MM Boulet, A Veilleux, S No?l, G Paris, A Tchernof. Abdominal subcutaneous and omental adipocyte morphology and its relation to gene expression, lipolysis and adipocytokine levels in women. Metabolism. 2014;63(3):372-381.
42	TJ Guzik, DS Skiba, RM Touyz, DG Harrison. The role of infiltrating immune cells in dysfunctional adipose tissue. Cardiovasc Res. 2017;113(9):1009-1023.
43	T Skurk, C Alberti-Huber, C Herder, H Hauner. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab. 2007;92(3):1023-1033.
44	MA Jimenez, P Akerblad, M Sigvardsson, ED Rosen. Critical role for Ebf1 and Ebf2 in the adipogenic transcriptional cascade. Mol Cell Biol. 2007;27(2):743-757.
45	MG Myers, SB Heymsfield, C Haft, et al. Challenges and opportunities of defining clinical leptin resistance. Cell Metab. 2012;15(2):150-156.
46	A La Cava, G Matarese. The weight of leptin in immunity. Nat Rev Immunol. 2004;4(5):371-379.
47	EA Rondini, JG Granneman. Single cell approaches to address adipose tissue stromal cell heterogeneity. Biochem J. 2020;477(3):583-600.
48	J Bilson, JK Sethi, CD Byrne. Heterogeneity of white adipocytes in metabolic disease. Curr Opin Clin Nutr Metab Care. 2023;26(2):72-77.
49	J B?ckdahl, L Franzén, L Massier, et al. Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin. Cell Metab. 2021;33(11):2301.
50	MP Emont, C Jacobs, AL Essene, et al. A single-cell atlas of human and mouse white adipose tissue. Nature. 2022;603(7903):926-933.
51	DS Cho, B Lee, JD Doles. Refining the adipose progenitor cell landscape in healthy and obese visceral adipose tissue using single-cell gene expression profiling. Life Sci Alliance. 2019;2(6):e201900561.
52	R Ferrero, P Rainer, B Deplancke. Toward a consensus view of mammalian adipocyte stem and progenitor cell heterogeneity. Trends Cell Biol. 2020;30(12):937-950.
53	PC Schwalie, H Dong, M Zachara, et al. A stromal cell population that inhibits adipogenesis in mammalian fat depots. Nature. 2018;559(7712):103-108.
54	D Merrick, A Sakers, Z Irgebay, et al. Identification of a mesenchymal progenitor cell hierarchy in adipose tissue. Science. 2019;364(6438):eaav2501.
55	H Leménager, LMA Fiévet, F Guilloton, et al. Cell immaturity and white/beige adipocyte potential of primary human adipose-derived stromal cells are restrained by culture-medium TGFβ1. Stem Cells. 2020;38(6):782-796.
56	L Vishvanath, KA MacPherson, C Hepler, et al. Pdgfrβ+ mural preadipocytes contribute to adipocyte hyperplasia induced by high-fat-diet feeding and prolonged cold exposure in adult mice. Cell Metab. 2016;23(2):350-359.
57	GC Rivera-Gonzalez, BA Shook, J Andrae, et al. Skin adipocyte stem cell self-renewal is regulated by a PDGFA/AKT-signaling axis. Cell Stem Cell. 2016;19(6):738-751.
58	C Sun, H Sakashita, J Kim, et al. Mosaic mutant analysis identifies PDGFRα/PDGFRβ as negative regulators of adipogenesis. Cell Stem Cell. 2020;26(5):707-721. e5.
59	KR Silva, LS Baptista. Adipose-derived stromal/stem cells from different adipose depots in obesity development. World J Stem Cells. 2019;11(3):147-166.
60	F Louwen, A Ritter, NN Kreis, J Yuan. Insight into the development of obesity: functional alterations of adipose-derived mesenchymal stem cells. Obes Rev. 2018;19(7):888-904.
61	C Hepler, B Shan, Q Zhang, et al. Identification of functionally distinct fibro-inflammatory and adipogenic stromal subpopulations in visceral adipose tissue of adult mice. Elife. 2018;7:e39636.
62	SR Farmer. Transcriptional control of adipocyte formation. Cell Metabolism. 2006;4(4):263-273.
63	J Lessard, S Laforest, M Pelletier, M Leboeuf, L Blackburn, A Tchernof. Low abdominal subcutaneous preadipocyte adipogenesis is associated with visceral obesity, visceral adipocyte hypertrophy, and a dysmetabolic state. Adipocyte. 2014;3(3):197-205.
64	LF Liu, CM Craig, LL Tolentino, et al. Adipose tissue macrophages impair preadipocyte differentiation in humans. PLoS One. 2017;12(2):e0170728.
65	Y Tchoukalova, C Koutsari, M Jensen. Committed subcutaneous preadipocytes are reduced in human obesity. Diabetologia. 2007;50(1):151-157.
66	AK Sárvári, EL Van Hauwaert, LK Markussen, et al. Plasticity of epididymal adipose tissue in response to diet-induced obesity at single-nucleus resolution. Cell Metabolism. 2021;33(2):437-453. e5.
67	E Andersen, LR Ingerslev, O Fabre, et al. Preadipocytes from obese humans with type 2 diabetes are epigenetically reprogrammed at genes controlling adipose tissue function. Int J Obes. 2019;43(2):306-318.
68	H Dong, W Sun, Y Shen, et al. Identification of a regulatory pathway inhibiting adipogenesis via RSPO2. Nat Metab. 2022;4(1):90-105.
69	SP Weisberg, D McCann, M Desai, M Rosenbaum, RL Leibel, AW Ferrante. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Investig. 2003;112(12):1796-1808.
70	H Xu, GT Barnes, Q Yang, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Investig. 2003;112(12):1821-1830.
71	I Harman-Boehm, M Blüher, H Redel, et al. Macrophage infiltration into omental versus subcutaneous fat across different populations: effect of regional adiposity and the comorbidities of obesity. J Clin Endocrinol Metab. 2007;92(6):2240-2247.
72	N Kamei, K Tobe, R Suzuki, et al. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem. 2006;281(36):26602-26614.
73	J Huber, FW Kiefer, M Zeyda, et al. CC chemokine and CC chemokine receptor profiles in visceral and subcutaneous adipose tissue are altered in human obesity. J Clin Endocrinol Metab. 2008;93(8):3215-3221.
74	M Keophiphath, C Rouault, A Divoux, K Clément, D Lacasa. CCL5 promotes macrophage recruitment and survival in human adipose tissue. Arterioscler Thromb Vasc Biol. 2010;30(1):39-45.
75	AA Hill, EK Anderson-Baucum, AJ Kennedy, CD Webb, FE Yull, AH Hasty. Activation of NF-κB drives the enhanced survival of adipose tissue macrophages in an obesogenic environment. Mol Metab. 2015;4(10):665-677.
76	S Gordon, PR Taylor. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5(12):953-964.
77	CN Lumeng, JB DelProposto, DJ Westcott, AR Saltiel. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes. 2008;57(12):3239-3246.
78	JM Wentworth, G Naselli, WA Brown, et al. Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes. 2010;59(7):1648-1656.
79	CN Lumeng, JL Bodzin, AR Saltiel. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Investig. 2007;117(1):175-184.
80	A Chawla, KD Nguyen, Y Goh. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol. 2011;11(11):738-749.
81	CN Lumeng, SM Deyoung, AR Saltiel. Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins. Am J Physiol Endocrinol Metab. 2007;292(1):E166-E174.
82	FO Martinez, S Gordon. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014;6:13.
83	L Russo, CN Lumeng. Properties and functions of adipose tissue macrophages in obesity. Immunology. 2018;155(4):407-417.
84	M Kratz, BR Coats, KB Hisert, et al. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metabolism. 2014;20(4):614-625.
85	DA Hill, H-W Lim, YH Kim, et al. Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue. Proc Natl Acad Sci USA. 2018;115(22):E5096-E5105.
86	DA Hill, HW Lim, YH Kim, et al. Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue. Proc Natl Acad Sci USA. 2018;115(22):E5096-e5105.
87	RM Pirzgalska, E Seixas, JS Seidman, et al. Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat Med. 2017;23(11):1309-1318.
88	DA Jaitin, L Adlung, CA Thaiss, et al. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell. 2019;178(3):686-698. e14.
89	A Weinstock, EJ Brown, ML Garabedian, et al. Single-cell RNA sequencing of visceral adipose tissue leukocytes reveals that caloric restriction following obesity promotes the accumulation of a distinct macrophage population with features of phagocytic cells. Immunometabolism. 2019;1:e190008.
90	AD Hildreth, F Ma, YY Wong, R Sun, M Pellegrini, TE O'Sullivan. Single-cell sequencing of human white adipose tissue identifies new cell states in health and obesity. Nat Immunol. 2021;22(5):639-653.
91	A Diefenbach, M Colonna, S Koyasu. Development, differentiation, and diversity of innate lymphoid cells. Immunity. 2014;41(3):354-365.
92	SH Wong, JA Walker, HE Jolin, et al. Transcription factor RORα is critical for nuocyte development. Nat Immunol. 2012;13(3):229-236.
93	E Vivier, D Artis, M Colonna, et al. Innate lymphoid cells: 10 years on. Cell. 2018;174(5):1054-1066.
94	G Eberl, M Colonna, JP Di Santo, AN McKenzie. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology. Science. 2015;348(6237):aaa6566.
95	TE O'Sullivan, M Rapp, X Fan, et al. Adipose-resident group 1 innate lymphoid cells promote obesity-associated insulin resistance. Immunity. 2016;45(2):428-441.
96	S Boulenouar, X Michelet, D Duquette, et al. Adipose type one innate lymphoid cells regulate macrophage homeostasis through targeted cytotoxicity. Immunity. 2017;46(2):273-286.
97	H Wang, L Shen, X Sun, et al. Adipose group 1 innate lymphoid cells promote adipose tissue fibrosis and diabetes in obesity. Nat Commun. 2019;10(1):3254.
98	JR Brestoff, BS Kim, SA Saenz, et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature. 2015;519(7542):242-246.
99	AB Molofsky, JC Nussbaum, HE Liang, et al. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med. 2013;210(3):535-549.
100	MW Lee, JI Odegaard, L Mukundan, et al. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell. 2015;160(1-2):74-87.
101	C Rosales, CA Lowell, M Schnoor, E Uribe-Querol. Neutrophils: Their role in innate and adaptive immunity. J Immunol Res. 2017;2017:9748345.
102	H Rhee, T Love, D Harrington. Blood neutrophil count is associated with body mass index in adolescents with asthma. JSM Allergy Asthma. 2018;3(1):1019.
103	C Gállego-Suárez, A Bulan, E Hirschfeld, et al. Enhanced myeloid leukocytes in obese children and adolescents at risk for metabolic impairment. Front Endocrinol (Lausanne). 2020;11:327.
104	JA Kim, HS Park. White blood cell count and abdominal fat distribution in female obese adolescents. Metabolism. 2008;57(10):1375-1379.
105	J Nijhuis, SS Rensen, Y Slaats, FM van Dielen, WA Buurman, JW Greve. Neutrophil activation in morbid obesity, chronic activation of acute inflammation. Obesity (Silver Spring). 2009;17(11):2014-2018.
106	TJ Shah, CE Leik, SW Walsh. Neutrophil infiltration and systemic vascular inflammation in obese women. Reprod Sci. 2010;17(2):116-124.
107	HM Roberts, MM Grant, N Hubber, P Super, R Singhal, ILC Chapple. Impact of bariatric surgical intervention on peripheral blood neutrophil (PBN) function in obesity. Obes Surg. 2018;28(6):1611-1621.
108	V Elgazar-Carmon, A Rudich, N Hadad, R Levy. Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res. 2008;49(9):1894-1903.
109	A Asghar, N Sheikh. Role of immune cells in obesity induced low grade inflammation and insulin resistance. Cell Immunol. 2017;315:18-26.
110	V Dam, T Sikder, S Santosa. From neutrophils to macrophages: differences in regional adipose tissue depots. Obes Rev. 2016;17(1):1-17.
111	W Trim, JE Turner, D Thompson. Parallels in immunometabolic adipose tissue dysfunction with ageing and obesity. Front Immunol. 2018;9:169.
112	AM Blaszczak, A Jalilvand, WA Hsueh. Adipocytes, innate immunity and obesity: a mini-review. Front Immunol. 2021;12:650768.
113	V Mansuy-Aubert, QL Zhou, X Xie, et al. Imbalance between neutrophil elastase and its inhibitor α1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure. Cell Metab. 2013;17(4):534-548.
114	S Talukdar, DY Oh, G Bandyopadhyay, et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med. 2012;18(9):1407-1412.
115	J Banchereau, F Briere, C Caux, et al. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767-811.
116	J Lu, J Zhao, H Meng, X Zhang. Adipose tissue-resident immune cells in obesity and type 2 diabetes. Front Immunol. 2019;10:1173.
117	BU Schraml, C Reis e Sousa. Defining dendritic cells. Curr Opin Immunol. 2015;32:13-20.
118	CE Macdougall, EG Wood, J Loschko, et al. Visceral adipose tissue immune homeostasis is regulated by the crosstalk between adipocytes and dendritic cell subsets. Cell Metab. 2018;27(3):588-601. e4.
119	M Merad, P Sathe, J Helft, J Miller, A Mortha. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol. 2013;31:563-604.
120	A Bertola, T Ciucci, D Rousseau, et al. Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes. 2012;61(9):2238-2247.
121	KW Cho, BF Zamarron, LA Muir, et al. Adipose tissue dendritic cells are independent contributors to obesity-induced inflammation and insulin resistance. J Immunol. 2016;197(9):3650-3661.
122	M Stefanovic-Racic, X Yang, MS Turner, et al. Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c+ cells in adipose tissue and liver. Diabetes. 2012;61(9):2330-2339.
123	N Pamir, NC Liu, A Irwin, et al. Granulocyte/macrophage colony-stimulating factor-dependent dendritic cells restrain lean adipose tissue expansion. J Biol Chem. 2015;290(23):14656-14667.
124	Y Chen, J Tian, X Tian, et al. Adipose tissue dendritic cells enhances inflammation by prompting the generation of Th17 cells. PLoS One. 2014;9(3):e92450.
125	VZ Rocha, EJ Folco, G Sukhova, et al. Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ Res. 2008;103(5):467-476.
126	T Deng, CJ Lyon, LJ Minze, et al. Class II major histocompatibility complex plays an essential role in obesity-induced adipose inflammation. Cell Metab. 2013;17(3):411-422.
127	DA Winer, S Winer, MH Chng, L Shen, EG Engleman. B Lymphocytes in obesity-related adipose tissue inflammation and insulin resistance. Cell Mol Life Sci. 2014;71(6):1033-1043.
128	P Srikakulapu, CA McNamara. B lymphocytes and adipose tissue inflammation. Arterioscler Thromb Vasc Biol. 2020;40(5):1110-1122.
129	DA Winer, S Winer, L Shen, et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med. 2011;17(5):610-617.
130	WV Trim, L Lynch. Immune and non-immune functions of adipose tissue leukocytes. Nat Rev Immunol. 2022;22(6):371-386.
131	S Ivanov, J Merlin, MKS Lee, AJ Murphy, RR Guinamard. Biology and function of adipose tissue macrophages, dendritic cells and B cells. Atherosclerosis. 2018;271:102-110.
132	J DeFuria, AC Belkina, M Jagannathan-Bogdan, et al. B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc Natl Acad Sci USA. 2013;110(13):5133-5138.
133	W Ying, J Wollam, JM Ofrecio, et al. Adipose tissue B2 cells promote insulin resistance through leukotriene LTB4/LTB4R1 signaling. J Clin Invest. 2017;127(3):1019-1030.
134	W Ying, A Tseng, RC Chang, et al. miR-150 regulates obesity-associated insulin resistance by controlling B cell functions. Sci Rep. 2016;6:20176.
135	X Zhai, G Qian, Y Wang, et al. Elevated B cell activation is associated with type 2 diabetes development in obese subjects. Cell Physiol Biochem. 2016;38(3):1257-1266.
136	D Frasca, A Diaz, M Romero, et al. Identification and characterization of adipose tissue-derived human antibodies with “anti-self” specificity. Front Immunol. 2020;11:392.
137	D Frasca, A Diaz, M Romero, S Thaller, BB Blomberg. Secretion of autoimmune antibodies in the human subcutaneous adipose tissue. PLoS One. 2018;13(5):e0197472.
138	DB Harmon, P Srikakulapu, JL Kaplan, et al. Protective role for B-1b B cells and IgM in obesity-associated inflammation, glucose intolerance, and insulin resistance. Arterioscler Thromb Vasc Biol. 2016;36(4):682-691.
139	L Shen, MH Chng, MN Alonso, R Yuan, DA Winer, EG Engleman. B-1a lymphocytes attenuate insulin resistance. Diabetes. 2015;64(2):593-603.
140	S Nishimura, I Manabe, S Takaki, et al. Adipose natural regulatory B cells negatively control adipose tissue inflammation. Cell Metab. 2013;18(5):759-766.
141	MP Cancro. Age-associated B cells age-associated B cells. Annu Rev Immunol. 2020;38:315-340.
142	D Frasca, A Diaz, M Romero, BB Blomberg. Phenotypic and functional characterization of double negative B cells in the blood of individuals with obesity. Front Immunol. 2021;12:616650.
143	T H?ggl?f, C Vanz, A Kumagai, et al. T-bet+ B cells accumulate in adipose tissue and exacerbate metabolic disorder during obesity. Cell Metab. 2022;34(8):1121-1136. e6.
144	MA Van Herck, J Weyler, WJ Kwanten, et al. The differential roles of T cells in non-alcoholic fatty liver disease and obesity. Front Immunol. 2019;10:82.
145	H Wu, S Ghosh, XD Perrard, et al. T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation. 2007;115(8):1029-1038.
146	A O'Garra, D Robinson. Development and function of T helper 1 cells. Adv Immunol. 2004;83:133-162.
147	IM Khan, XY Dai Perrard, JL Perrard, et al. Attenuated adipose tissue and skeletal muscle inflammation in obese mice with combined CD4+ and CD8+ T cell deficiency. Atherosclerosis. 2014;233(2):419-428.
148	E Stolarczyk, CT Vong, E Perucha, et al. Improved insulin sensitivity despite increased visceral adiposity in mice deficient for the immune cell transcription factor T-bet. Cell Metab. 2013;17(4):520-533.
149	KY Kim, HJ Jeong, HM Kim. The role of T-bet in obesity: lack of T-bet causes obesity in male mice. J Nutr Biochem. 2013;24(1):240-247.
150	J Zhu, WE Paul. CD4 T cells: fates, functions, and faults. Blood. 2008;112(5):1557-1569.
151	S Winer, Y Chan, G Paltser, et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med. 2009;15(8):921-929.
152	CP Hong, A Park, BG Yang, et al. Gut-specific delivery of T-Helper 17 cells reduces obesity and insulin resistance in mice. Gastroenterology. 2017;152(8):1998-2010.
153	M Sumarac-Dumanovic, D Stevanovic, A Ljubic, et al. Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women. Int J Obes (Lond). 2009;33(1):151-156.
154	LA Zú?iga, WJ Shen, B Joyce-Shaikh, et al. IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J Immunol. 2010;185(11):6947-6959.
155	JB Pandolfi, AA Ferraro, I Sananez, et al. ATP-induced inflammation drives tissue-resident Th17 cells in metabolically unhealthy obesity. J Immunol. 2016;196(8):3287-3296.
156	M Feuerer, L Herrero, D Cipolletta, et al. but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 2009;15(8):930-939.
157	A Vasanthakumar, K Moro, A Xin, et al. The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells. Nat Immunol. 2015;16(3):276-285.
158	D Kolodin, N van Panhuys, C Li, et al. Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab. 2015;21(4):543-557.
159	K Eller, A Kirsch, AM Wolf, et al. Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy. Diabetes. 2011;60(11):2954-2962.
160	D Cipolletta, M Feuerer, A Li, et al. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature. 2012;486(7404):549-553.
161	JM Han, D Wu, HC Denroche, Y Yao, CB Verchere, MK Levings. IL-33 reverses an obesity-induced deficit in visceral adipose tissue ST2+ T regulatory cells and ameliorates adipose tissue inflammation and insulin resistance. J Immunol. 2015;194(10):4777-4783.
162	H Luck, S Tsai, J Chung, et al. Regulation of obesity-related insulin resistance with gut anti-inflammatory agents. Cell Metab. 2015;21(4):527-542.
163	D Bradley, AJ Smith, A Blaszczak, et al. Interferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity. Nat Commun. 2022;13(1):5606.
164	T McLaughlin, LF Liu, C Lamendola, et al. T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arterioscler Thromb Vasc Biol. 2014;34(12):2637-2643.
165	MH Andersen, D Schrama, P Thor Straten, JC Becker. Cytotoxic T cells. J Invest Dermatol. 2006;126(1):32-41.
166	S Nishimura, I Manabe, M Nagasaki, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009;15(8):914-920.
167	ME Rausch, S Weisberg, P Vardhana, DV Tortoriello. Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes (Lond). 2008;32(3):451-463.
168	N Kawanishi, T Mizokami, H Yano, K Suzuki. Exercise attenuates M1 macrophages and CD8+ T cells in the adipose tissue of obese mice. Med Sci Sports Exerc. 2013;45(9):1684-1693.
169	K Man, A Kallies, A Vasanthakumar. Resident and migratory adipose immune cells control systemic metabolism and thermogenesis. Cell Mol Immunol. 2022;19(3):421-431.
170	S Virtue, A Vidal-Puig. Adipose tissue expandability, lipotoxicity and the metabolic syndrome–an allostatic perspective. Biochim Biophys Acta. 2010;1801(3):338-349.
171	N Hosogai, A Fukuhara, K Oshima, et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes. 2007;56(4):901-911.
172	L Vona-Davis, DP Rose. Angiogenesis, adipokines and breast cancer. Cytokine Growth Factor Rev. 2009;20(3):193-201.
173	D Ribatti, A Vacca, B Nico, M Presta, L Roncali. Angiogenesis: basic and clinical aspects. Ital J Anat Embryol. 2003;108(1):1-24.
174	A Engin. Adipose tissue hypoxia in obesity and its impact on preadipocytes and macrophages: hypoxia hypothesis. Adv Exp Med Biol. 2017;960:305-326.
175	K Sun, J Tordjman, K Clément, E Scherer Philipp. Fibrosis and adipose tissue dysfunction. Cell Metab. 2013;18(4):470-477.
176	MF Gregor, GS Hotamisligil. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415-445.
177	SM Reilly, AR Saltiel. Adapting to obesity with adipose tissue inflammation. Nat Rev Endocrinol. 2017;13(11):633-643.
178	MTA Nguyen, S Favelyukis, A-K Nguyen, et al. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem. 2007;282(48):35279-35292.
179	JY Lee, L Zhao, HS Youn, et al. Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J Biol Chem. 2004;279(17):16971-16979.
180	H Kwon, JE Pessin. Adipokines mediate inflammation and insulin resistance. Front Endocrinol. 2013;4:71.
181	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. 2005;46(11):2347-2355.
182	S Nishimura, I Manabe, M Nagasaki, et al. Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells, and blood vessels. Diabetes. 2007;56(6):1517-1526.
183	S Nishimura, I Manabe, M Nagasaki, et al. In vivo imaging in mice reveals local cell dynamics and inflammation in obese adipose tissue. J Clin Investig. 2008;118(2):710-721.
184	KJ Strissel, Z Stancheva, H Miyoshi, et al. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes. 2007;56(12):2910-2918.
185	B Vandanmagsar, Y-H Youm, A Ravussin, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011;17(2):179-188.
186	J Ye, Z Gao, J Yin, Q He. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab. 2007;293(4):E1118-E1128.
187	P Quintero, P González-Muniesa, DF García-Díaz, JA Martínez. Effects of hyperoxia exposure on metabolic markers and gene expression in 3T3-L1 adipocytes. J Physiol Biochem. 2012;68(4):663-669.
188	Q He, Z Gao, J Yin, J Zhang, Z Yun, J Ye. Regulation of HIF-1{alpha} activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia. Am J Physiol Endocrinol Metab. 2011;300(5):E877-E885.
189	P Trayhurn, B Wang, IS Wood. Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? Br J Nutr. 2008;100(2):227-235.
190	C Celik, SYT Lee, WS Yap, G Thibault. Endoplasmic reticulum stress and lipids in health and diseases. Prog Lipid Res. 2023;89:101198.
191	M Schr?der, RJ Kaufman. ER stress and the unfolded protein response. Mutat Res. 2005;569(1):29-63.
192	A Dasgupta, GK Bandyopadhyay, I Ray, et al. Catestatin improves insulin sensitivity by attenuating endoplasmic reticulum stress: in vivo and in silico validation. Comput Struct Biotechnol J. 2020;18:464-481.
193	S Park, A Jang, SG Bouret. Maternal obesity-induced endoplasmic reticulum stress causes metabolic alterations and abnormal hypothalamic development in the offspring. PLoS Biol. 2020;18(3):e3000296.
194	Y Chen, Z Wu, S Zhao, R Xiang. Chemical chaperones reduce ER stress and adipose tissue inflammation in high fat diet-induced mouse model of obesity. Sci Rep. 2016;6:27486.
195	JH Kim, E Lee, RH Friedline, et al. Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity. Faseb J. 2018;32(4):2292-2304.
196	NK Sharma, SK Das, AK Mondal, et al. Endoplasmic reticulum stress markers are associated with obesity in nondiabetic subjects. J Clin Endocrinol Metab. 2008;93(11):4532-4541.
197	KM Mair, R Gaw, MR MacLean. Obesity, estrogens and adipose tissue dysfunction—implications for pulmonary arterial hypertension. Pulm Circ. 2020;10(3):2045894020952019.
198	A Chait, LJ den Hartigh. Adipose tissue distribution, inflammation and its metabolic consequences, including diabetes and cardiovascular disease. Front Cardiovasc Med. 2020;7:22.
199	B Ahmed, R Sultana, MW Greene. Adipose tissue and insulin resistance in obese. Biomed Pharmacother. 2021;137:111315.
200	JA Paniagua. Nutrition, insulin resistance and dysfunctional adipose tissue determine the different components of metabolic syndrome. World J Diab. 2016;7(19):483-514.
201	SE Shoelson, J Lee, AB Goldfine. Inflammation and insulin resistance. J Clin Investig. 2006;116(7):1793-1801.
202	B Li, JC Leung, LY Chan, WH Yiu, SC Tang. A global perspective on the crosstalk between saturated fatty acids and Toll-like receptor 4 in the etiology of inflammation and insulin resistance. Progr Lipid Res. 2020;77:101020.
203	Z Gao, D Hwang, F Bataille, et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor κB kinase complex. J Biol Chem. 2002;277(50):48115-48121.
204	JM Zabolotny, Y-B Kim, LA Welsh, EE Kershaw, BG Neel, BB Kahn. Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo. J Biol Chem. 2008;283(21):14230-14241.
205	Y Watanabe, Y Nagai, K Takatsu. Activation and regulation of the pattern recognition receptors in obesity-induced adipose tissue inflammation and insulin resistance. Nutrients. 2013;5(9):3757-3778.
206	L Lukic, NM Lalic, N Rajkovic, et al. Hypertension in obese type 2 diabetes patients is associated with increases in insulin resistance and IL-6 cytokine levels: potential targets for an efficient preventive intervention. Int J Environ Res Public Health. 2014;11(4):3586-3598.
207	SE Kahn, RL Hull, KM Utzschneider. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444(7121):840-846.
208	K Chang-Chen, R Mullur, E Bernal-Mizrachi. β-cell failure as a complication of diabetes. Rev Endocr Metab Disord. 2008;9:329-343.
209	T Ogihara, RG Mirmira. An islet in distress: β cell failure in type 2 diabetes. J Diab Investig. 2010;1(4):123-133.
210	Y Matsuzawa, I Shimomura, T Nakamura, Y Keno, K Kotani, K Tokunaga. Pathophysiology and pathogenesis of visceral fat obesity. Obes Res. 1995;3(S2):187s-194s.
211	WY Fujimoto, SL Abbate, SE Kahn, JE Hokansno, JD Brunzell. The visceral adiposity syndrome in Japanese-American men. Obes Res. 1994;2(4):364-371.
212	BLo Wajchenberg. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocrine Reviews. 2000;21(6):697-738.
213	N Abate, A Garg, RM Peshock, J Stray-Gundersen, SM Grundy. Relationships of generalized and regional adiposity to insulin sensitivity in men. J Clin Investig. 1995;96(1):88-98.
214	N Abate, A Garg, RM Peshock, J Stray-Gundersen, B Adams-Huet, SM Grundy. Relationship of generalized and regional adiposity to insulin sensitivity in men with NIDDM. Diabetes. 1996;45(12):1684-1693.
215	BH Goodpaster, F Leland Thaete, J-A Simoneau, DE Kelley. Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fat. Diabetes. 1997;46(10):1579-1585.
216	I Ferreira, RM Henry, JW Twisk, W van Mechelen, HC Kemper, CD Stehouwer. The metabolic syndrome, cardiopulmonary fitness, and subcutaneous trunk fat as independent determinants of arterial stiffness: the Amsterdam Growth and Health Longitudinal Study. Arch Intern Med. 2005;165(8):875-882.
217	T McLaughlin, A Deng, O Gonzales, et al. Insulin resistance is associated with a modest increase in inflammation in subcutaneous adipose tissue of moderately obese women. Diabetologia. 2008;51:2303-2308.
218	M Snijder, M Visser, J Dekker, et al. Low subcutaneous thigh fat is a risk factor for unfavourable glucose and lipid levels, independently of high abdominal fat. The Health ABC Study. Diabetologia. 2005;48:301-308.
219	M Snijder, PZ Zimmet, M Visser, J Dekker, J Seidell, JE Shaw. Independent and opposite associations of waist and hip circumferences with diabetes, hypertension and dyslipidemia: the AusDiab Study. Int J Obes. 2004;28(3):402-409.
220	CC Curioni, PM Louren?o. Long-term weight loss after diet and exercise: a systematic review. Int J Obes (Lond). 2005;29(10):1168-1174.
221	S Wharton, DCW Lau, M Vallis, et al. Obesity in adults: a clinical practice guideline. Cmaj. 2020;192(31):E875-e891.
222	MD Jensen, DH Ryan, CM Apovian, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129:S102-S138. 25 Suppl 2.
223	MS Savova, LV Mihaylova, D Tews, M Wabitsch, MI Georgiev. Targeting PI3K/AKT signaling pathway in obesity. Biomed Pharmacother. 2023;159:114244.
224	X Huang, G Liu, J Guo, Z Su. The PI3K/AKT pathway in obesity and type 2 diabetes. Int J Biol Sci. 2018;14(11):1483-1496.
225	X Wen, B Zhang, B Wu, et al. Signaling pathways in obesity: mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2022;7(1):298.
226	P Liu, W Gan, YR Chin, et al. PtdIns(3,4,5)P3-dependent activation of the mTORC2 kinase complex. Cancer Discov. 2015;5(11):1194-1209.
227	BA Hemmings, DF Restuccia. PI3K-PKB/Akt pathway. Cold Spring Harb Perspect Biol. 2012;4(9):a011189.
228	S Nagai, C Matsumoto, M Shibano, K Fujimori. Suppression of fatty acid and triglyceride synthesis by the flavonoid orientin through decrease of C/EBPδ expression and inhibition of PI3K/Akt-FOXO1 signaling in adipocytes. Nutrients. 2018;10(2):130.
229	X Chen, C Yu, X Liu, et al. Intracellular galectin-3 is a lipopolysaccharide sensor that promotes glycolysis through mTORC1 activation. Nat Commun. 2022;13(1):7578.
230	JS Brunner, A Vogel, A Lercher, et al. The PI3K pathway preserves metabolic health through MARCO-dependent lipid uptake by adipose tissue macrophages. Nat Metab. 2020;2(12):1427-1442.
231	N Kobayashi, K Ueki, Y Okazaki, et al. Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance. Proc Natl Acad Sci USA. 2011;108(14):5753-5758.
232	T Kassouf, G Sumara. Impact of conventional and atypical MAPKs on the development of metabolic diseases. Biomolecules. 2020;10(9):1256.
233	M Pal, MA Febbraio, GI Lancaster. The roles of c-Jun NH2-terminal kinases (JNKs) in obesity and insulin resistance. J Physiol. 2016;594(2):267-279.
234	AS Khan, S Subramaniam, G Dramane, D Khelifi, NA Khan. ERK1 and ERK2 activation modulates diet-induced obesity in mice. Biochimie. 2017;137:78-87.
235	F Bost, M Aouadi, L Caron, et al. The extracellular signal–regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adipogenesis. Diabetes. 2005;54(2):402-411.
236	J Hirosumi, G Tuncman, L Chang, et al. A central role for JNK in obesity and insulin resistance. Nature. 2002;420(6913):333-336.
237	J Chung, AK Nguyen, DC Henstridge, et al. HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci USA. 2008;105(5):1739-1744.
238	G Sabio, M Das, A Mora, et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science. 2008;322(5907):1539-1543.
239	MS Han, DY Jung, C Morel, et al. JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science. 2013;339(6116):218-222.
240	X Zeng, X Du, J Zhang, et al. The essential function of CARD9 in diet-induced inflammation and metabolic disorders in mice. J Cell Mol Med. 2018;22(6):2993-3004.
241	Z Wang, M Zhu, M Wang, et al. Integrated multiomic analysis reveals the high-fat diet induced activation of the MAPK signaling and inflammation associated metabolic cascades via histone modification in adipose tissues. Front Genet. 2021;12:650863.
242	HY Yong, MS Koh, A Moon. The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Expert Opin Investig Drugs. 2009;18(12):1893-1905.
243	C Chen, LJ Nelson, MA ávila, FJ Cubero. Mitogen-activated protein kinases (MAPKs) and cholangiocarcinoma: the missing link. Cells. 2019;8(10).
244	DG Hardie. AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels. Annu Rev Nutr. 2014;34:31-55.
245	B Xiao, MJ Sanders, D Carmena, et al. Structural basis of AMPK regulation by small molecule activators. Nat Commun. 2013;4(1):3017.
246	S Bijland, SJ Mancini, IP Salt. Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation. Clin Sci (Lond). 2013;124(8):491-507.
247	SM Jeon. Regulation and function of AMPK in physiology and diseases. Exp Mol Med. 2016;48(7):e245.
248	AE Pollard, L Martins, PJ Muckett, et al. AMPK activation protects against diet-induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue. Nat Metab. 2019;1(3):340-349.
249	XJ Xu, M-S Gauthier, DT Hess, et al. Insulin sensitive and resistant obesity in humans: aMPK activity, oxidative stress, and depot-specific changes in gene expression in adipose tissue. J Lipid Res. 2012;53(4):792-801.
250	EP Mottillo, EM Desjardins, JD Crane, et al. Lack of adipocyte AMPK exacerbates insulin resistance and hepatic steatosis through brown and beige adipose tissue function. Cell Metab. 2016;24(1):118-129.
251	L Wu, L Zhang, B Li, et al. AMP-activated protein kinase (AMPK) regulates energy metabolism through modulating thermogenesis in adipose tissue. Front Physiol. 2018;9:122.
252	AE Pollard, L Martins, PJ Muckett, et al. AMPK activation protects against diet induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue. Nat Metab. 2019;1(3):340-349.
253	T Luo, A Nocon, J Fry, et al. AMPK activation by metformin suppresses abnormal extracellular matrix remodeling in adipose tissue and ameliorates insulin resistance in obesity. Diabetes. 2016;65(8):2295-2310.
254	SS da Cruz Nascimento, JL Carvalho de Queiroz, A Fernandes de Medeiros, et al. Anti-inflammatory agents as modulators of the inflammation in adipose tissue: a systematic review. PLoS One. 2022;17(9):e0273942.
255	PS Hsieh, JS Jin, CF Chiang, PC Chan, CH Chen, KC Shih. COX-2-mediated inflammation in fat is crucial for obesity-linked insulin resistance and fatty liver. Obesity (Silver Spring). 2009;17(6):1150-1157.
256	L Ma, TW Liu, MA Wallig, et al. Efficient targeting of adipose tissue macrophages in obesity with polysaccharide nanocarriers. ACS Nano. 2016;10(7):6952-6962.
257	DT Furuya, AC Poletto, RR Favaro, JO Martins, TM Zorn, UF Machado. Anti-inflammatory effect of atorvastatin ameliorates insulin resistance in monosodium glutamate-treated obese mice. Metabolism. 2010;59(3):395-399.
258	A Mukherjee, S Mukherjee, J Biswas, M Roy. Phytochemicals in obesity control. Int J Curr Microbiol App Sci. 2015;4(4):558-567.
259	SK Chakrabarti, BK Cole, Y Wen, SR Keller, JL Nadler. 12/15-lipoxygenase products induce inflammation and impair insulin signaling in 3T3-L1 adipocytes. Obesity. 2009;17(9):1657-1663.
260	M Alsaggar, S Bdour, Q Ababneh, T El-Elimat, N Qinna, KH Alzoubi. Silibinin attenuates adipose tissue inflammation and reverses obesity and its complications in diet-induced obesity model in mice. BMC Pharmacol Toxicol. 2020;21:1-8.
261	M Gao, Y Ma, D Liu. Rutin suppresses palmitic acids-triggered inflammation in macrophages and blocks high fat diet-induced obesity and fatty liver in mice. Pharm Res. 2013;30:2940-2950.
262	V Natesan, SJ Kim. Lipid metabolism, disorders and therapeutic drugs—review. Biomol Ther (Seoul). 2021;29(6):596-604.
263	M Ruscica, N Ferri, RD Santos, CR Sirtori, A Corsini. Lipid lowering drugs: present status and future developments. Curr Atheroscler Rep. 2021;23(5):17.
264	YJ Tak, SY Lee. Anti-obesity drugs: long-term efficacy and safety: an updated review. World J Mens Health. 2021;39(2):208-221.
265	TD Müller, M Blüher, MH Tsch?p, RD DiMarchi. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov. 2022;21(3):201-223.
266	P Hallenborg, RK Petersen, I Kouskoumvekaki, JW Newman, L Madsen, K Kristiansen. The elusive endogenous adipogenic PPARγ agonists: lining up the suspects. Prog Lipid Res. 2016;61:149-162.
267	RE Soccio, ER Chen, MA Lazar. Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metab. 2014;20(4):573-591.
268	MS Malamas, J Sredy, I Gunawan, et al. New azolidinediones as inhibitors of protein tyrosine phosphatase 1B with antihyperglycemic properties. J Med Chem. 2000;43(5):995-1010.
269	R Maccari, P Paoli, R Ottanà, et al. 5-Arylidene-2,4-thiazolidinediones as inhibitors of protein tyrosine phosphatases. Bioorg Med Chem. 2007;15(15):5137-5149.
270	AP Combs, EW Yue, M Bower, et al. Structure-based design and discovery of protein tyrosine phosphatase inhibitors incorporating novel isothiazolidinone heterocyclic phosphotyrosine mimetics. J Med Chem. 2005;48(21):6544-6548.
271	JM Zabolotny, KK Bence-Hanulec, A Stricker-Krongrad, et al. PTP1B regulates leptin signal transduction in vivo. Dev Cell. 2002;2(4):489-495.
272	NK Tonks. PTP1B: from the sidelines to the front lines!. FEBS Lett. 2003;546(1):140-148.
273	KA Lantz, SGE Hart, SL Planey, et al. Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice. Obesity. 2010;18(8):1516-1523.
274	J Abbasi. Semaglutide's success could usher in a “new dawn” for obesity treatment. JAMA. 2021;326(2):121-123.
275	T Rodrigues, P Borges, L Mar, et al. GLP-1 improves adipose tissue glyoxalase activity and capillarization improving insulin sensitivity in type 2 diabetes. Pharmacol Res. 2020;161:105198.
276	J Chen, H Zhao, X Ma, et al. GLP-1/GLP-1R signaling in regulation of adipocyte differentiation and lipogenesis. Cell Physiol Biochem. 2017;42(3):1165-1176.
277	TD Challa, N Beaton, M Arnold, G Rudofsky, W Langhans, C Wolfrum. Regulation of adipocyte formation by GLP-1/GLP-1R signaling. J Biol Chem. 2012;287(9):6421-6430.
278	D Rubino, N Abrahamsson, M Davies, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. Jama. 2021;325(14):1414-1425.
279	M Davies, L F?rch, OK Jeppesen, et al. Semaglutide 2· 4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021;397(10278):971-984.
280	Centers for Disease Control and Prevention. Overweight & Obesity. State and Local Strategies. Accessed September 15, 2022, 2022.
281	M Morales-Suarez-Varela, E Collado Sánchez, I Peraita-Costa, A Llopis-Morales, JM Soriano. Intermittent fasting and the possible benefits in obesity, diabetes, and multiple sclerosis: a systematic review of randomized clinical trials. Nutrients. 2021;13(9):3179.
282	DL Swift, JE McGee, CP Earnest, E Carlisle, M Nygard, NM Johannsen. The effects of exercise and physical activity on weight loss and maintenance. Prog Cardiovasc Dis. 2018;61(2):206-213.
283	A Jacob, G Moullec, KL Lavoie, et al. Impact of cognitive-behavioral interventions on weight loss and psychological outcomes: a meta-analysis. Health Psychol. 2018;37(5):417.
284	K Shaw, P O'Rourke, C Del Mar, J Kenardy. Psychological interventions for overweight or obesity. Cochrane Database Syst Rev. 2005(2):Cd003818.
285	RE Ley, PJ Turnbaugh, S Klein, JI Gordon. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444(7122):1022-1023.
286	A Cotillard, SP Kennedy, LC Kong, et al. Dietary intervention impact on gut microbial gene richness. Nature. 2013;500(7464):585-588.
287	RV Bryant, SP Costello, SC Forster, S Santos-Paulo, SP Travis. The gut microbiota as a therapeutic target for obesity: a scoping review. Nutr Res Rev. 2022;35(2):207-220.
288	AS Bourinbaiar, V Jirathitikal. Effect of oral immunization with pooled antigens derived from adipose tissue on atherosclerosis and obesity indices. Vaccine. 2010;28(15):2763-2768.
289	KN Haffer. Effects of novel vaccines on weight loss in diet-induced-obese (DIO) mice. J Anim Sci Biotechnol. 2012;3(1):21.
290	M Gao, D Liu. Gene therapy for obesity: progress and prospects. Discov Med. 2014;17(96):319-328.
291	AM Angelidi, MJ Belanger, A Kokkinos, CC Koliaki, CS Mantzoros. Novel noninvasive approaches to the treatment of obesity: from pharmacotherapy to gene therapy. Endocr Rev. 2021;43(3):507-557.
292	JY Chung, QU Ain, Y Song, SB Yong, YH Kim. Targeted delivery of CRISPR interference system against Fabp4 to white adipocytes ameliorates obesity, inflammation, hepatic steatosis, and insulin resistance. Genome Res. 2019;29(9):1442-1452.