Review and Commentary: Research Advances in Adipose Tissue and the Pathogenesis of Obesity-Related Hypertension

FENG Jia¹, LYU Yao¹, ZHOU Yiheng¹, BAI Jiaxin¹, LIU Lidi¹, ZHAO Qian¹, LEI Yi¹, JIA Yu¹, LIAO Xiaoyang¹,²

¹Department of General Practice Medicine/Teaching and Research Section of General Practice/General Practice Medical Research Laboratory, West China Hospital of Sichuan University, Chengdu 610041, China
²Department of General Practice Medicine Special Needs Ward for General Practice, West China Hospital of Sichuan University, Chengdu 610041, China

*Corresponding authors: LIAO Xiaoyang, Professor/Doctoral supervisor; E-mail: liaoxiaoyang@wchscu.cn
JIA Yu, Research assistant; E-mail: jiayu@wchscu.cn

Abstract

The global prevalence of obesity-related hypertension is rising sharply, drawing significant attention in the medical field. Obesity complicates blood pressure control, promotes cardiovascular and cerebrovascular damage, and increases disease burden. Abnormal expansion and remodeling of adipose tissue, considered central to obesity, are closely linked to hypertension pathogenesis through mechanisms including renin-angiotensin-aldosterone system activation, adipokine imbalance, inflammatory responses, sympathetic nervous system activation, and insulin resistance. Given the strong heterogeneity and complexity of adipose tissue's functional classification, anatomical distribution, and endocrine effects, this review systematically examines current knowledge on adipose tissue, focusing on its classification, distribution, and pathological mechanisms in relation to obesity-related hypertension. We summarize current research evidence and future directions to provide new insights for basic and clinical research on obesity-related hypertension and to inspire investigation of novel therapeutic targets.

Keywords: Obesity; Hypertension; Obesity-related hypertension; Adipose tissue; Pathological mechanisms; Review

Obesity-related hypertension refers to hypertension closely associated with obesity, with effective weight control being a key characteristic that can reduce arterial blood pressure [1]. According to WHO surveys, by 2016, the global number of obese individuals had approximately doubled since 1975 [2], and in 2020, about 39 million children under five were overweight or obese [2]. In 2010, 31% of adults worldwide had hypertension, affecting 1.39 billion people, and the global prevalence continues to rise due to population aging and increased lifestyle risk factors [3]. Numerous studies have confirmed that overweight and obesity are major risk factors for hypertension and adverse cardiovascular events [4-6]. The Framingham Heart Study demonstrated that 65% of primary hypertension in women and 78% in men could be attributed to weight gain [7], with hypertension prevalence reaching 61-77% in overweight and obese patients [8]. In China, obesity-related hypertension and its associated cardiometabolic risks are also increasing. ZHANG et al. [9] analyzed data from the China Health and Retirement Longitudinal Study (CHARLS) and found that in 2015, the prevalence of obesity-related hypertension among Chinese adults aged 45 and above was 22.7%, affecting approximately 120 million people and accounting for 66% of all hypertension cases. SUN et al. [10] projected that by 2030, the prevalence of overweight/obesity and hypertension among Chinese adults would reach 71% and 35%, respectively.

As the primary organ for energy storage, large-scale expansion and remodeling of adipose tissue are considered core pathological manifestations of obesity [11]. Adipose tissue is a dynamic organ distributed throughout the body, located in subcutaneous and visceral regions, and composed of adipocytes, pre-adipocytes, mesenchymal stem cells, fibroblasts, blood vessels, nerves, macrophages, and immune cells [12]. Human adipose tissue can be classified based on cellular composition and function into white adipose tissue (WAT), brown adipose tissue (BAT), and beige adipose tissue. Its distribution involves multiple body sites, and current research indicates that different fat depots have distinct pathological mechanisms and significance in cardiovascular diseases such as hypertension [13]. Obesity-induced hypertension involves multiple neuroendocrine mechanisms, including dysregulation of vasoactive adipokines and pro-inflammatory factors, hyperinsulinemia and insulin resistance, and kidney injury. As researchers have deepened their understanding of adipose tissue, it has become clear that dysfunction in any of its three major functions—lipid storage, endocrine function, and insulin responsiveness—can significantly impact cardiometabolic health [12]. Therefore, this review synthesizes recent research on adipose tissue based on its functional classification, anatomical distribution, and mechanisms of action in the pathogenesis of obesity-related hypertension, aiming to deepen understanding of this field and provide insights for prevention and treatment.

1 Adipose Tissue Expansion and Functional Classification

Adipose tissue responds to energy excess through two dynamic mechanisms: hyperplasia and hypertrophy, with regulatory characteristics and metabolic impacts showing significant variation by age, sex, and fat depot distribution. Adipocyte hyperplasia occurs primarily through proliferation and differentiation of pre-adipocytes into new adipocytes, a process notably active before adulthood, especially in abdominal subcutaneous adipose tissue [14]. Research confirms that subcutaneous fat depots form a protective expansion pattern through continuous generation of metabolically flexible small adipocytes, effectively delaying insulin resistance and inflammation [15-16]. After adulthood, pre-adipocyte proliferation capacity declines significantly, activating only partially under specific stimuli such as long-term high-fat diet [17]. Adipocyte hypertrophy, characterized by expansion of existing cell volume and adipose tissue remodeling, shows a marked predilection in visceral fat depots [18-19]. Compared with hyperplasia, pathological hypertrophy demonstrates stronger correlation with obesity-related metabolic risk: when lipid storage capacity is exceeded, hypertrophic adipocytes trigger ectopic lipid deposition through a "spillover" effect of free fatty acids, leading to lipotoxicity, insulin resistance, and type 2 diabetes in non-adipose tissues [20].

1.1 WAT

WAT is the main form of adipose tissue in humans [21]. It serves not only as an energy storage site but also as a highly active endocrine organ that secretes nitric oxide, leptin, and other adipokines and mediators, exerting autocrine, paracrine, and endocrine effects on neighboring cells or distant tissues and organs. WAT accumulation, particularly visceral deposition, is a key determinant of increased relative risk for hypertension and cardiovascular disease. Additionally, as total fat increases, deposition of epicardial and perivascular WAT also increases [22-24], with their physiological functions further elaborated in the discussion of adipose tissue distribution.

1.2 BAT

BAT is a specialized adipose tissue that, unlike WAT, is relatively scarce in adults, accounting for 4.3% of total fat mass. In adults, BAT is found in cervical, supraclavicular, axillary, paraspinal, mediastinal, and abdominal regions [25] as well as in perivascular adipose tissue (PVAT) [26]. BAT consists of stromal tissue, white adipocytes, and thermogenic adipocytes containing uncoupling protein 1, functioning as a thermogenic organ. Recent studies show BAT is negatively correlated with individual risk of hypertension and coronary artery disease [27]. A retrospective study revealed that individuals with detectable BAT had lower prevalence of cardiometabolic diseases and adverse cardiac events, with BAT's beneficial effects being more pronounced in overweight or obese individuals [27]. An animal study that created interscapular BAT-deficient mice through surgical resection demonstrated that these mice had significantly higher blood pressure and more severe vascular injury compared to wild-type mice [28]. Additionally, prospective studies suggest BAT's cardiovascular benefits may relate to cold-activated BAT increasing energy expenditure and enhancing glucose and free fatty acid processing [29,30]. BAT also secretes various molecules that modify BAT itself or remotely affect other organs through autocrine, paracrine, and endocrine mechanisms. For example, fibroblast growth factor 21 (FGF21) secreted by BAT helps counteract angiotensin II-induced blood pressure and vascular function changes and may activate peroxisome proliferator-activated receptor γ, ultimately stimulating adiponectin production to exert beneficial effects on the cardiovascular system and blood pressure regulation [31]. However, clinical studies have yet to demonstrate a direct effect of BAT on blood pressure control, requiring further investigation.

1.3 Beige Adipose Tissue

Researchers have identified a unique type of adipocyte in WAT upon cold exposure or β-adrenergic receptor activation, termed beige adipocytes, a phenomenon known as "WAT browning" [32,33]. Beige adipose tissue is mainly distributed in the neck, supraclavicular, axillary, and paraspinal regions. Similar to brown adipocytes, beige adipocytes can exhibit a thermogenic phenotype resembling BAT in response to various stimuli (such as cold, endocrine factors, or compounds). Animal experiments show that during cold exposure, beige adipose tissue can display high uncoupling protein 1 expression and high energy consumption similar to brown adipocytes [34]. Researchers have therefore hypothesized that inducing WAT browning into beige adipose tissue may reduce obesity-related complications. For instance, activation of BAT and beige adipose tissue may be an effective strategy for treating obesity and type 2 diabetes. Regardless of sex or age, subjects with detectable cold-activated BAT had lower average BMI, body weight, and waist circumference [35]. In type 2 diabetic mice, β-adrenergic-induced BAT activation significantly reduced blood glucose levels, although similar results were not observed in the WAT browning group [36]. Furthermore, PERSSON et al. [37] demonstrated that β3-adrenergic agonist-induced browning of perivascular WAT maintained PVAT's anti-contractile effects, improved endothelial function, and reduced hypertension development. Current strategies commonly used to induce WAT browning include cold exposure, pharmacological agents, and exercise. However, research on whether beige adipose tissue improves obesity and its complications remains limited to animal studies, and several questions must be addressed to explore its clinical significance: whether enhancing thermogenesis alone is sufficient for weight loss, whether it may compensatorily increase energy intake, whether browning pathways are adipose tissue-specific, and what the overall effects of their activation and blockade are [38].

2 Adipose Tissue Distribution and Obesity-Related Hypertension

Based on anatomical location, adipose tissue can be divided into subcutaneous adipose tissue (SAT) and ectopic fat deposition (EFD). EFD can be further categorized into visceral adipose tissue (VAT) and PVAT [39]. Numerous studies suggest that fat distribution in specific locations shows stronger associations with cardiovascular risk than total fat volume [40]. Therefore, analyzing the relationship between body fat distribution and the pathology of obesity-related hypertension is of great significance.

2.1 SAT and VAT

SAT is located beneath the skin, while VAT refers to fat surrounding internal organs [41], including abdominal and thoracic adipose tissue. Abdominal VAT is further subdivided into mesenteric, peritoneal, and retroperitoneal (perirenal) adipose tissue; thoracic VAT includes epicardial adipose tissue (EAT), pericardial adipose tissue, and non-pericardial thoracic adipose tissue (any thoracic location outside the pericardium) [42]. When energy intake exceeds expenditure, excess free fatty acids and glycerol are stored as triglycerides in SAT [43,44]. However, SAT's expansion capacity is limited and genetically determined. Once this capacity is exceeded, VAT accumulation is promoted or lipids deposit in non-adipose tissues (such as liver and muscle), leading to hepatic steatosis and increased intramyocellular lipid content, which promotes cardiometabolic complications of obesity [45].

Extensive rodent and human studies demonstrate that visceral obesity is associated with metabolic syndrome [46], including arterial hypertension (nocturnal or persistent), metabolic syndrome, insulin resistance, impaired glucose metabolism, type 2 diabetes, dyslipidemia, and steatohepatitis [47]. VAT accumulation (intra-abdominal, mediastinal, epicardial, and cervical regions) positively correlates with cardiometabolic disease risk, whereas SAT accumulation (gluteofemoral region) shows no such correlation or even negatively correlates with risk [48]. Therefore, identifying molecular mechanisms controlling adipose tissue expansion and reversing adipose tissue remodeling during obesity may be key to improving obesity-related complications.

2.2 Perirenal Adipose Tissue (PRAT)

PRAT is a retroperitoneal fat pad surrounding the kidneys and adrenal glands, located between the renal capsule and renal fascia [49]. Multiple studies link PRAT to hypertension. Hypertensive patients have greater PRAT thickness than normotensive individuals (13.6±4.8 mm vs. 1.6±4.1 mm), and PRAT thickness positively correlates with elevated systolic blood pressure [50]. In another cross-sectional study of 42 overweight and obese patients, PRAT thickness independently correlated with 24-hour mean diastolic blood pressure [51]. INOKUCHI et al. [52] showed that PRAT thickening was more pronounced in patients with obesity-related complications (chronic kidney disease, cardiovascular disease, hypertension, and type 2 diabetes), suggesting PRAT's involvement in obesity pathogenesis.

Three potential mechanisms are thought to underlie PRAT's blood pressure regulation: physical compression, paracrine effects, and neurohumoral regulation [53]. Excessive intra-abdominal and retroperitoneal fat may compress the kidneys, increasing intrarenal pressure, altering renal hemodynamics, and inducing tissue hypoxia, subsequently leading to renal dysfunction and hypertension [54]. LI et al. [57] found that surgical removal of mouse PRAT significantly increased renal cortical blood flow. Additionally, persistent renal compression activates the RAAS. Previous studies also suggested that excess visceral fat increases intra-abdominal pressure and correlates with systemic hypertension, though this view lacks recent support [71].

Due to oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress, ectopic fat tissue around the kidneys may transmit lipotoxic immune and endocrine effects [55]. Adipokines released from adipose tissue may promote inflammation and enhance RAAS activity, increasing renal sodium and water reabsorption [56]. Furthermore, PRAT afferent nerves in blood pressure regulation have recently attracted widespread attention [57]. Although only cross-sectional studies have demonstrated the close relationship between PRAT and elevated blood pressure, PRAT represents a potential target for hypertension management, and further research is needed to clarify causality.

2.3 Epicardial Adipose Tissue (EAT)

EAT is a unique fat depot between the heart's surface and the visceral pericardium, with distinct structural and functional characteristics that significantly influence coronary artery disease, atrial fibrillation, heart failure, and hypertension [58]. Research shows that EAT accumulation leads to secretion of numerous pro-inflammatory cytokines and vasoactive peptides, such as tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1 (MCP-1), and angiotensin (Ang) II, which can activate RAAS and raise blood pressure [13]. Additionally, reduced adiponectin levels in EAT impair endothelium-mediated vasodilation, potentially promoting hypertension [59]. EAT also produces and releases large amounts of free fatty acids, increasing plasma catecholamine concentrations and activating the cardiac autonomic nervous system, thereby elevating blood pressure [60]. A recent meta-analysis by GUAN et al. [61] showed that hypertensive patients had higher EAT measurements (SMD=1.07, 95%CI=0.66-1.48; I²=89.2%), with each 1 mm increase in EAT raising the risk of impaired blood pressure circadian rhythm by 2.55-fold. Two cross-sectional studies also demonstrated close relationships between EAT volume and hypertension in children and adolescents [62]. However, prospective studies revealing causal relationships between EAT and hypertension development are lacking and warrant further investigation.

2.4 Perivascular Adipose Tissue (PVAT)

PVAT is adipose tissue surrounding blood vessels, primarily located around arteries and veins with diameters >50 μm [63]. PVAT not only fills and protects blood vessels but also regulates vascular tone, participates in local inflammatory responses, and influences metabolic processes. Adipocytes surround nearly every blood vessel in the body, secreting numerous metabolically and vasoactive adipokines [42]. In healthy states, PVAT exerts vasodilatory, antioxidant, and anti-inflammatory effects on the vasculature [64], mainly by secreting vasodilators such as adiponectin, apelin, leptin, and omentin, acting directly on vascular smooth muscle cells' relaxation and contraction properties [76].

In obesity, dysfunctional adipose tissue leads to dysregulated adipokine secretion. On one hand, adipocyte hypertrophy causes local hypoxia, activating hypoxia-inducible factors that promote release of inflammatory factors like TNF-α and IL-6 while inhibiting adiponectin secretion, thereby diminishing its anti-hypertensive effects [77]. On the other hand, overactivation of RAAS in adipose tissue of obese patients increases Ang II generation, further stimulating release of pro-hypertensive factors like leptin and resistin [72]. Therefore, imbalance between pro-hypertensive and anti-hypertensive adipokines may promote obesity-related hypertension development through inflammation, vascular dysfunction, and sympathetic nervous system activation.

3 Pathological Mechanisms

3.1 Physical Mechanisms

Increased body fat in obesity may cause biomechanical/structural abnormalities at the physical level. For example, PRAT, enclosed by renal fascia, may directly compress renal parenchyma when overgrown, elevating intrarenal pressure, altering renal hemodynamics, and inducing tissue hypoxia, leading to subsequent renal dysfunction and hypertension [69,70]. LI et al. [57] found that surgical removal of mouse PRAT significantly increased renal cortical blood flow. Additionally, persistent renal compression stimulates RAAS activation. Previous studies also suggested that excess visceral fat increases intra-abdominal pressure and correlates with systemic hypertension, though this view lacks recent research support [71].

3.2 Adipokines

Adipokines are bioactive substances secreted by adipose tissue. Based on current research, adipokines can be divided into pro-hypertensive and anti-hypertensive categories. Pro-hypertensive adipokines include not only classic leptin and resistin but also recently identified factors such as chemerin, visfatin, and retinol-binding protein 4 that may correlate with hypertension development [72-73]. Anti-hypertensive adipokines include adiponectin and Omentin-1 [74-75]. Some studies also suggest that reactive oxygen species, leptin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and apelin possess both vasoconstrictive and vasodilatory properties [76].

In obesity, dysfunctional adipose tissue leads to dysregulated adipokine secretion. Adipocyte hypertrophy causes local hypoxia, activating hypoxia-inducible factors that promote release of inflammatory factors like TNF-α and IL-6 while inhibiting adiponectin secretion, thereby diminishing its anti-hypertensive effects [77]. Additionally, overactivation of RAAS in adipose tissue of obese patients increases Ang II generation, further stimulating release of pro-hypertensive factors like leptin and resistin [72]. Therefore, imbalance between pro-hypertensive and anti-hypertensive adipokines may promote obesity-related hypertension development through inflammation, vascular dysfunction, and sympathetic nervous system activation.

3.3 RAAS

RAAS comprises two pathways: a pro-inflammatory pathway involving the angiotensin-converting enzyme (ACE)/Ang II/angiotensin receptor 1 (AT1)/aldosterone/mineralocorticoid receptor (MR) axis, and an anti-inflammatory pathway involving the angiotensin receptor 2 (AT2)/ACE2/Ang1-7/Mas receptor axis [78-79]. Activation of the pro-inflammatory pathway may lead to excessive hypertension and cardiorenal risk in obese patients. Obesity is associated with mild-to-moderate increases in systemic and local adipose RAAS activity [69]. Angiotensinogen is produced not only by the liver but also by various adipose tissue depots, including subcutaneous and visceral adipose tissue and PVAT. In obesity, angiotensinogen secretion from these tissues increases, which can be converted to Ang II with strong vasoconstrictive effects, raising blood pressure by increasing peripheral vascular resistance. Adipocytes in obese individuals may also produce aldosterone, and their synergistic action further elevates blood pressure. Multiple studies demonstrate RAAS activity in both white and brown PVAT [80], though the role of adipose-derived Ang II in obesity-related hypertension remains unclear [69].

3.4 Hyperinsulinemia and Insulin Resistance

Hyperinsulinemia and insulin resistance also play important roles in obesity-related hypertension [81]. Several studies in experimental animals and humans show that hyperinsulinemia can increase sympathetic nervous system activity, activate RAAS, and promote sodium and water retention, potentially raising blood pressure if persistent [82]. Insulin acts on nearly all nephron segments and is an agonist for sodium reabsorption. The sodium-proton exchanger type 3 on the luminal side of proximal tubules, the basolateral sodium-bicarbonate cotransporter in proximal tubules, and epithelial sodium channels in distal nephron segments and connecting tubules are all regulated by insulin [83]. Insulin may also raise blood pressure by stimulating the sympathetic nervous system; studies prove that when obese patients reduce insulin through low-energy diets, both blood pressure and sympathetic nervous system activity decrease [84]. Additionally, when insulin resistance causes hyperglycemia and tissue oxidative stress, it accelerates glycation processes, and advanced glycation end-products indirectly cause hypertension by increasing oxidative stress and RAAS activity [85].

Conclusion

This review systematically analyzed the complex roles of adipose tissue functional types, anatomical distribution, and pathological mechanisms in obesity-related hypertension. Adipose tissue expansion, classification, and distribution are closely related to adipocyte function, playing distinct roles in hypertension. Adipose tissue exhibits strong heterogeneity, and its fat mass, distribution, and type are interrelated, significantly increasing pathological complexity. Furthermore, adipose tissue involvement in hypertension pathogenesis includes not only endocrine and paracrine effects but also physical compression impacts, which may relate to hemodynamics and mechanical stress. Abnormal accumulation of adipose tissue around the kidneys, heart, and blood vessels correlates with hypertension severity, indicating that ectopic adipose tissue is a key pathogenic factor. The limited expansion capacity of subcutaneous adipose tissue determines the characteristics of visceral and intra-organ fat accumulation, suggesting that adipose tissue expansion mechanisms are critical for regulating obesity-related complications and may represent future hypertension intervention targets.

However, current research on the direct relationship between adipose tissue classification/distribution and hypertension consists mainly of preclinical and cross-sectional studies, with few prospective studies and even fewer interventional trials. Future research should adopt precision medicine approaches to deeply analyze different adipose phenotype transitions and pathogenic mechanisms, providing new directions for obesity-related hypertension research and therapeutic strategies.

Author Contributions: FENG Jia was responsible for conceptualization, literature collection, and manuscript writing. LYU Yao, ZHOU Yiheng, BAI Jiaxin, LIU Lidi, ZHAO Qian, LEI Yi, and LIAO Xiaoyang contributed to manuscript revision. JIA Yu was responsible for quality control and final review.

Conflict of Interest: The authors declare no conflicts of interest.

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(Received: 2024-08-13; Revised: 2025-03-31)
(Editor: ZOU Lin)