Gender differences in adiponectin levels among obese individuals and their association with cardiovascular disease

Figures

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  FIGURE 1. Adiponectin associated signaling pathways. Adiponectin acts on three receptors: AdipoR1, AdipoR2, and T-cadherin. APPL1 is a ligation protein that assists in mediating the adiponectin pathway. AdipoR1 can further phosphorylate p38MAPK by binding to APPL1 and further activate PPARα. AMPK can also be activated via LKB and PLC; AdipoR2 can bind to APPL1, activate PPARα, and further activate Acyl-CoA oxidase (ACO), an enzyme that catalyzes the first step of fatty acid peroxisome β-oxidation and makes the rate determine the step. T-cadherin can bind to APPL1 to activate the AMPK and Notch pathways. AdipoR1/2, adiponectin receptor 1/2; APPL1, adaptor protein containing PH domain, PTB domain and leucine zipper motif 1; AMPK, AMP-activated protein kinase; LKB1, liver kinase B1; eNOS, endothelial nitric oxide synthase; MAPK, Mitogen-activated protein kinase; NO, nitric oxide; ACC, acetyl-CoA carboxylase; PPARα, peroxisome proliferator-activated receptor alpha; ACO, acyl-CoA oxidase; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; PLC, phospholipase C; IP3, inositol 1,4,5-trisphosphate; CaMKK, Ca2+/calmodulin-dependent protein kinase; GLUT4, glucose transporter type 4.

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  FIGURE 2. Gender differences the pathophysiological changes of adipocytes. This schematic illustrates the proposed progression: (1) Compensated cellular hypertrophy leads to relative hypoxia and HIF activation. (2) This initiates angiogenic and profibrotic responses (e.g., VEGF, COL6). (3) Ultimately, these processes exceed compensatory capacity, resulting in extracellular matrix dissolution, aberrant fibrotic remodeling, and sustained inflammation. Arrows indicate proposed stimulatory relationships. Abbreviations: COL6, Collagen VI; HIF-1alpha, Hypoxia-Inducible Factor-1Alpha; M1, Macrophage Type 1; IL-6, Interleukin-6; MMP14, Matrix Metalloproteinase-14; TGF-beta, Transforming Growth Factor-Beta; TNF-alpha, Tumor Necrosis Factor-Alpha.

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  FIGURE 3. Hormonal changes in people with obesity adiponectin. This schematic compares sex-dependent differences in adipose tissue distribution and function in obesity. In females, estrogen promotes a gynoid fat distribution pattern characterized by enhanced adipose tissue browning, increased adiponectin secretion, and activation of the APPL1-AMPK signaling axis. These changes are associated with improved mitochondrial function, enhanced oxidative capacity, and an overall anti-inflammatory metabolic state. In contrast, male obesity is characterized by an android fat distribution pattern, reduced adipose browning capacity, decreased adiponectin levels, and impaired APPL1-PPARα signaling. These alterations are associated with increased reactive oxygen species production, macrophage M1 polarization driven by IL-6, and a chronic pro-inflammatory state. Together, these sex-specific differences provide a mechanistic framework for the generally lower cardiometabolic risk observed in women with obesity compared with men. Abbreviations: ROS, reactive oxygen species.

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  FIGURE 4. Adiponectin in cardiac remodelling and the progression of heart failure. The figure contrasts the pathogenic mechanisms driven by dysfunctional cardiac-associated adipose tissue against the cardiometabolic benefits mediated by adiponectin signaling. It further contextualizes the paradoxical association of high adiponectin levels with poor prognosis in advanced cardiovascular disease. The pink area primarily represents the effects of adiponectin, while the blue area mainly indicates the roles of EAT and PAVT. Abbreviations: Acta2, Actin alpha 2, smooth muscle; Ang, Angiotensi; CVD, Cardiovascular disease; EAT, Epicardial adipose tissue; HFpEF, Heart failure with preserved ejection fraction; HFrEF, Heart failure with reduced ejection fraction ILK, Integrin-linked kinase; M1/M2, Macrophage type 1/2; MPO, Myeloperoxidase; mTOR, Mammalian target of rapamycin; NP, Natriuretic peptide; PDK4, Pyruvate dehydrogenase kinase 4; PVAT, Perivascular adipose tissue; SDH, Succinate dehydrogenase; sT-cad, Soluble T-cadherin; STAT3, Signal transducer and activator of transcription 3; YAP, Yes-associated protein.