Studies have shown that sensory nerves and sympathetic nerve fibers play a dominant role in regulating adipose function. Sympathetic nerve endings regulate adipocyte function through the release of factors such as norepinephrine, neuropeptide Y (NPY) and ATP (62), β-adrenergic receptors (βAR) are channels that mobilize fat for consumption in other tissues, and their activation promotes lipolysis of stored triglycerides in white and brown adipocytes (63). Norepinephrine-mediated lipolysis in white adipose tissue is dependent on β-adrenoceptor stimulation and ultimately on hormone-sensitive lipase and phospholipid A phosphorylation. And in addition to controlling lipolysis, the increase or decrease of norepinephrine inhibits and stimulates white adipocyte proliferation, respectively (64). In contrast to norepinephrine, NPY promotes adipocyte differentiation and lipid accumulation, leading to energy storage in adipose tissue, whose effects are mediated mainly through NPY receptor subtypes 1 and 2 (65).

The endocannabinoid system (ECS) plays a key role in the development of obesity, and blocking type 1 cannabinoid receptors can reduce body weight and attenuate metabolic disorders associated with obesity. Adipocyte production of endocannabinoids negatively regulates adiposympathetic innervation, thereby inhibiting brown adipose tissue thermogenesis and promoting white adipose tissue accumulation (66). In addition, adipocyte-secreted BMP8b ² mediates adrenergic-induced remodeling of neurovascular networks in adipose tissue. The innervation and vascular remodeling effects require BMP8b signaling through adipocytes to secrete neuromodulatory protein-4 (NRG4) ³ , which promotes sympathetic axon growth and branch formation in vitro ( 67). In addition, adipocytes also secrete various neurotrophic factors such as nerve growth factor and S100 calcium-binding protein b (S100b) to promote synapse growth and S100b to innervate thermogenic adipose tissue (68–70).

Adipocytes produce a large number of pro-angiogenic factors, including fibroblast growth factor 2 (FGF-2), VEGF, hepatocyte growth factor (HGF) and PDGF (71). Studies have shown that exposure of mice to cold leads to activation of angiogenesis in white and brown adipose tissue, with upregulation of pro-angiogenic factors such as VEGF and downregulation of endogenous angiogenic inhibitors including thrombomodulin. reduction of VEGFR2 abolished cold-induced angiogenesis and significantly impaired non-shivering thermogenesis. reduction of VEGFR1 led to the opposite effect: increased adipose tissue vascularity and non-shivering thermogenic capacity was increased (72). VEGFA in brown adipocytes is a highly specific and potent angiogenic factor that promotes the specificity of vascular endothelial cell proliferation, migration and survival, VEGFA overexpression enhances mitochondrial respiration and thermogenesis, VEGFB plays an important role in adipose tissue vascular remodeling and specifically controls endothelial uptake of fatty acids through transcriptional regulation of vascular fatty acid transport proteins (73).

Endothelin-1 (ET-1) and epidermal growth factor (EGF) secreted by vascular endothelial cells have important regulatory effects on adipocytes. They block the expression of C/EBPα and the adipose marker PPARγ, there by inhibiting adipogenesis. Additionally, Endothelin-1 inhibits the differentiation of human and mouse adipocyte progenitor cells (74). Endothelin-1 has a direct effect on adipocytes, and long-term treatment of adipocytes with endothelin-1 in vitro leads to desensitization of insulin signaling, resulting in reduced glucose transport. Endothelin-1 stimulates lipolysis by binding to endothelin receptor A (75). Plasma endothelin-1 levels are elevated in patients with obesity and type 2 diabetes, but the primary source of circulating endothelin-1 in these conditions is unknown (76). Studies have shown that nitric oxide secreted by vascular endothelial cells can induce vascular smooth muscle relaxation through guanylate cyclase activation and cyclic GMP formation, thereby promoting vasodilation and enhancing thermogenesis (77). Nitric oxide can regulate the number and function of mitochondria in brown adipocytes and various cell lines. Mitochondria play a key role in brown adipose thermogenesis, so nitric oxide can affect adipose thermogenesis (78).

Local infiltration of immune cells and production of pro-inflammatory cytokines can contribute to obesity and insulin resistance, with macrophages being most closely associated with obesity and insulin resistance (79). Macrophages can exhibit both M1 and M2 phenotypes, and the transition from an anti-inflammatory M2-like phenotype to a pro-inflammatory M1-like phenotype is believed to be the primary cause of adipose tissue inflammation in obese patients. In addition, the number of macrophages is positively correlated with insulin resistance (80). Local infiltration of immune cells and increased production of pro-inflammatory cytokines contribute to the development of insulin resistance in obesity. Compared to white adipose tissue, brown adipose tissue is less susceptible to local inflammation caused by obesity. However, the production of pro-inflammatory cytokines can ultimately lead to a pro-inflammatory environment in brown fat, which can directly impact its thermogenic activity by impairing energy expenditure mechanisms and disrupting glucose metabolism. This is thought to contribute to the development of obesity-related metabolic disorders (81). Interleukin-1 beta (IL-1β) is a typical pro-inflammatory cytokine released by M1 macrophages. Its mRNA expression levels are upregulated in the white adipose tissue of obese mice and RAW264.7 macrophages. IL-1β can inhibit the expression of uncoupling protein 1 (UCP1) induced by beta-adrenergic receptor stimulation in adipocytes, which impairs thermogenic function both in vivo and in vitro ( 82).

The browning process of beige adipocytes is associated with an increase in anti-inflammatory M2 macrophages, but the function of M2 macrophages in the browning process and their underlying mechanisms are not fully understood. It has been shown that the macrophage cytokine Slit3 binds to ROBO1 receptors on sympathetic neurons and activates tyrosine hydrolase (TH) via PKA and CaMKII signaling, thereby stimulating the synthesis and release of norepinephrine, which acts on adipocytes and stimulates thermogenesis (83). Mechanistically, macrophages in white adipose tissue undergo alternative activation under cold stress, which induces the expression of tyrosine hydroxylase and the production of catecholamines. These catecholamines are required for the process of white adipose tissue browning (84). In one study, tyrosine hydroxylase expression was not detected in macrophage populations isolated from brown adipose tissue and white adipose tissue after cold exposure. This suggests that alternatively activated M2 macrophages may be the source of catecholamines in white adipose tissue (85).

CXCL14 (C-X-C motif chemokine ligand 14) ⁴ , also known as Breast and Kidney-expressed chemokine (BRAK), was identified in a 2018 study as a novel regulatory factor secreted during the thermogenic activation of brown fat cells. CXCL14 released by brown fat cells recruits alternatively activated M2 macrophages and promotes browning of white fat in high-fat diet-induced obese mice, leading to improved glucose and insulin homeostasis (86). It has also been shown that lipocalin enhances cold-induced subcutaneous adipose tissue browning by promoting M2 macrophage proliferation (87).

The central nervous system is able to integrate feeding information to influence feeding behavior and long-term energy homeostasis (88). The hypothalamus is involved in thermoregulation by activating brown adipose tissue in response to peripheral cold-sensing signals, resulting in non- shivering thermogenesis (89). The hypothalamus also contributes to the maintenance of body temperature by driving sympathetic activation that allows the release of norepinephrine from nerve terminals innervating the BAT, which activates the intracellular lipolytic cascade and releases fatty acids that fuel the brown fat mitochondrial electron transport chain (90) ( Figure 2 ).

Thermogenesis of BAT is activated by the hypothalamus via the sympathetic nervous system. Norepinephrine, a key neurotransmitter mediating activation, binds to the b3-adrenoceptor (b3 AR) to increase cAMP levels, thereby rapidly activating protein kinase A (PKA) and hormone-sensitive lipase (HSL)-mediated lipolysis. It has been shown that CNS activation for BAT thermogenesis is mainly associated with the thyroid hormone T3, which regulates the thermogenic program in brown adipose tissue (BAT) via AMP-activated protein kinase (AMPK) in the ventral medial nucleus of the hypothalamus (VMH). In addition, T3 acting in the paraventricular nucleus of the hypothalamus (PVH) also regulates glucose homeostasis in the liver (91). T3 also regulates thermogenesis by inducing the expression of the UCP1 gene (92) ( Figure 2 ).

Estrogen-mediated central actions also play an important role for BAT, and it has been shown that estradiol (E2) can regulate energy homeostasis by reducing hypothalamic ceramide levels and endoplasmic reticulum (ER) stress. Most of the effects of estradiol on feeding occur in pre-opioid melanopsin (POMC) neurons in the hypothalamic arcuate nucleus, but regulation of thermogenesis in BAT occurs in the ventral medial nucleus of the hypothalamus (24). A 2015 study showed that insulin and leptin ⁵ secreted by adipocytes acting together on hypothalamic neurons can promote WAT browning and weight loss. The mechanism of action is that leptin acts on the POMC to suppress food intake and increase energy expenditure by promoting thermogenesis in the BAT, and leptin action in the hypothalamus increases sympathetic activity in the BAT, as well as increases UCP-1 expression. Insulin acts on the POMC to regulate systemic glucose metabolism and trigger an anorexic response (93).

Glucocorticoids are a class of steroidal compounds synthesized and secreted by the fasciculata zone of the adrenal cortex. In vivo, the hypothalamic-anterior pituitary-adrenocortical axis primarily regulates glucocorticoid secretion. It was once demonstrated that in rodents, glucocorticoids inhibit UCP1 expression in brown adipocytes; however, this demonstration was overturned in a 2019 study (94). Glucocorticoids have opposite effects in humans and rodents, and the glucocorticoid prednisolone sharply increased fluorodeoxyglucose uptake via BAT in healthy men under mild cold exposure. In addition, prednisolone increased human supraclavicular skin temperature and energy expenditure during cold exposure. And glucocorticoids increased isoprenaline-stimulated respiration and UCP-1 in human primary brown adipocytes, but significantly decreased isoprenaline-stimulated respiration and UCP-1 in murine primary brown and beige adipocytes (95). A study using positron emission tomography/computed tomography (PET/CT) to noninvasively study BAT activity and brain glucose metabolism in vivo found that neuropeptide Y (NPY) secreted by the hypothalamus mediates brain glucose metabolism consistent with BAT activity in healthy adults (96) ( Figure 2 ).

BAT is thought to have a role in improving heart function, and the presence of BAT is negatively associated with the incidence of heart disease (97). The dysfunction of brown adipose tissue refers to the inability of brown adipose tissue in the body to function properly, leading to a disorder in energy metabolism. The characteristic of BAT dysfunction associated with UCP1 deficiency is impaired thermogenic capacity. In a catecholamine-induced myocardial injury model in mice, UCP1 deficiency resulted in BAT dysfunction, increased myocardial cell injury and adverse left ventricular remodeling in mice, and decreased survival in a mouse model of catecholamine-induced cardiomyopathy. Transplantation of functional BAT into UCP1-deficient mice rescued myocardial injury as well as increased survival (98) ( Figure 3 ).

Ectopic adipose tissue can also negatively impact cardiac function. Research studies have shown that epicardial adipose tissue (EAT) may have a potential impact on cardiovascular (CV) risk (99–102). Abnormal adipogenesis in the epicardium can lead to the secretion of pro-inflammatory adipokines, which can in turn lead to atrial and ventricular fibrosis (99). Thicker and dysfunctional epicardial adipose tissue (EAT) can promote the development and progression of coronary atherosclerosis. In addition, EAT may release mediators directly into the vessels of the coronary artery wall through a process known as “vascular secretion.” The pro-inflammatory and pro-fibrotic effects of dysfunctional EAT may ultimately impair cardiac structure and function (100).

The adenosine A2A receptor is a type of G protein-coupled receptor that plays an important role in the cardiovascular system. In mice, knockdown of the adenosine A2A receptor leads to BAT dysfunction, which can in turn accelerate cardiac remodeling in hypertension. Brown adipose tissue is capable of secreting fibroblast growth factor 21 (FGF21) ⁶ , which can in turn influence cardiac function. Studies have shown that knockdown of FGF21 specifically in brown adipocytes can attenuate the modulatory effects of A2A receptor agonists on cardiac remodeling in hypertension. Conversely, activation of the A2A receptor in BAT can promote the release of FGF21 and improve cardiac function. This finding reveals an endocrine role of BAT in hypertensive cardiac remodeling through secretion of cytokines activating the A2AR/FGF21 pathway (8) ( Figure 3 ). IL-6 ⁷ release from BAT increased cardiac matrix oxidation and protected the heart from hypertrophy and oxidative stress (10) ( Figure 3 ). In addition, brown adipose tissue can modulate cardiac function by releasing adipokines such as 12,13-diHOME ⁸ . Studies have shown that overexpression of 12,13-diHOME can counteract the deleterious effects of a high-fat diet on cardiac function and remodeling. Furthermore, acute injection of 12,13-diHOME has been shown to increase cardiac hemodynamics through direct effects on cardiomyocytes (11) ( Figure 3 ). Leptin secreted by adipose tissue is an adipokine with pleiotropic effects that are associated with cardioprotection. Leptin overexpression in mouse models was found to counteract inflammation in the heart and adipose tissue by regulating gene expression (103).

Natriuretic peptides, including atrial natriuretic peptide (ANP) and ventricular natriuretic peptide (BNP), can be produced by the heart ( Figure 3 ). Both activate PPARγ coactivator-1α (PGC-1α) ⁹ and UCP1 expression in human adipocytes, induce mitochondrial production, and increase uncoupling and total respiration. At low concentrations, ANP and β-adrenoceptor agonists were added to enhance the expression of brown adipose and mitochondrial markers in a p38 MAPK-dependent manner. Infusion of BNP into mice significantly increased the expression of UCP1 and PGC-1α in white adipose and brown adipose tissues and increased respiration and energy expenditure (25).

Neuromodulatory protein 4 (Nrg4) is highly expressed in brown adipose tissue, and it has been shown to reduce insulin resistance and hepatic steatosis by attenuating hepatic adipogenic signaling. Mechanistically, Nrg4 activates ErbB3/ErbB4 signaling in hepatocytes and regulates LXR/SREBP1c-mediated de novo adipogenesis in a cell-autonomous manner (17). A 2019 study showed that alcohol consumption stimulates hypothalamic neural circuits and sympathetic nerves innervating BAT and increases BAT uncoupling protein 1 expression and activity in a BAT sympathetic-dependent manner, thereby inhibiting lipid transport to the liver, suggesting that brown adipose tissue activation attenuates alcohol-induced hepatic steatosis and injury in mice. Brown adipocytes also secretes the adiponectin ¹⁰ to inhibit hepatocyte injury and death (18). Leptin secreted by adipose tissue has a role in regulating diet and energy metabolism, and exogenous administration of leptin modulates the activity of water channel proteins thereby ameliorating nonalcoholic fatty liver disease (NAFLD) in mice, while leptin restores the coordinated action of Aquaporin-9(AQP9), thereby preventing excessive lipid accumulation in the liver in WAT and obesity (13) ( Figure 4 ).

Adipose tissue serves as a major source of circulating exosomal miRNAs that are associated with improved glucose tolerance and hepatic FGF21 levels (104). FGF21 mediates a bidirectional communication axis between BAT and liver, and hepatic FGF21 contributes to thermogenic activation of brown fat in neonates (105). Patatin-like phospholipase domain-containing protein 3 (PNPLA3) is an adipocyte-specific nutrient-regulating transmembrane protein in mice called adiponectin (106), a hepatic lipase with triglyceride hydrolase activity. Replacement of isoleucine at protein position 148 by methionine can lead to loss of PNPLA3 function and hinder remodeling of monounsaturated and polyunsaturated fatty acid esters in favor of retention in the liver, which is an important factor contributing to the development of fatty liver (107) ( Figure 4 ).

The liver, through metabolic conversion, can produce acylcarnitine to provide fuel for brown fat thermogenesis. White adipose tissue provides the liver with long-chain fatty acids, allowing the liver to produce plasma acylcarnitine as a fuel source for peripheral tissues in mice (108). The liver also contributes to energy consumption through other endocrine pathways, and it has been shown that hepatic secretion of bile acids induces energy expenditure by promoting intracellular thyroid hormone activation. The increased energy expenditure in brown adipose tissue observed after the administration of bile acids to mice can prevent obesity and insulin resistance, and it has been demonstrated that this effect is mediated by the BA-TGR5-cAMP-D2 signaling pathway (26) ( Figure 4 ).

Hepatocyte surface expression of sodium-taurocholic acid cotransport protein (NTCP) reduces hepatic clearance of plasma bile acids, increases plasma bile acid levels, reduces diet-induced obesity, attenuates hepatic steatosis, and lowers plasma cholesterol levels. NTCP, G protein-coupled bile acid receptor (TGR5) double knockout mice are equally protected from diet-induced obesity as NTCP single knockout mice. NTCP deficiency was associated with increased uncoupled respiration in brown adipose tissue, leading to increased energy expenditure (109) ( Figure 4 ). Bile acids are also involved in TGR5 signaling promoting mitochondrial division and beige remodeling in white adipose tissue (27).

Certain enzymes present in the liver also play an active role in thermogenesis and weight maintenance. Hepatic fructose-1,6-bisphosphatase (FBP) is a regulatory enzyme in gluconeogenesis, and an increase in FBP reduces food intake by 15% without reducing energy expenditure. The decrease in food consumption was associated with increased levels of leptin and fatty acid oxidation, decreased appetite stimulating neuropeptide, neuropeptide Y (110). Cholesteryl ester transfer protein (CETP), which is synthesized by the liver, can also reduce obesity by enhancing lipolysis and brown adipose tissue activity (28). All of the above studies have shown that crosstalk between the liver and adipose tissue is necessary to maintain liver function and systemic energy homeostasis ( Figure 4 ).

Myokines are a collection of cytokines and other small proteins released by skeletal muscles. Skeletal muscles can synthesize and secrete various myokines (111) ( Figure 5 ). It has been shown that exercise promotes BAT activation, as well as white adipose tissue deposition to the subcutis and WAT browning (29) ( Figure 5 ). Exercise induces the secretion of myokines to mediate crosstalk between adipose tissue and skeletal muscle. Studies have shown that exercise induces IL-6 secretion in skeletal muscle, which regulates WAT and skeletal muscle metabolism and helps maintain metabolic homeostasis during exercise recovery (30). It has been shown that IL-6 injection can increase iWAT UCP1 mRNA content in WT mice (31). Exercise can also induce thermogenesis by inducing the production of other myokines, irisin, a hormone-like myokine that is produced in large amounts in skeletal muscle during exercise, acts on white adipocytes to induce a browning response and subsequently activates non-shivering thermogenesis (32). β-aminoisobutyric acid (BAIBA) is a myokine that increases in plasma concentrations after exercise, and promotes the activation of brown adipose tissue, as well as the browning of white adipose tissue. BAIBA also induces lipolysis by increasing FFA oxidation in adipocytes’ mitochondria (33).

Nickel riboflavin (METRNL) is a circulating factor induced in muscle after exercise and in adipose tissue after cold exposure. increased METRNL at circulating levels stimulates energy expenditure, improves glucose tolerance, and is associated with expression of genes related to thermogenic and anti-inflammatory cytokines in beige fat. Its mechanism of action is to stimulate increased IL-4 expression and promote selective activation of adipose tissue macrophages, leading to increased thermogenic and anti-inflammatory gene expression (34). Brain-derived neurotrophic factor (BDNF) is a kind of neurotrophic factor that is widely distributed in multiple regions of the central nervous system (CNS), including the cerebral cortex and hippocampus. A study has discussed the impact of aerobic exercise on BDNF. In the experiment, rats were engaged in aerobic exercise, and it was found that aerobic exercise could increase the levels of BDNF. This indicates a close relationship between BDNF and exercise (112). Stimulating the hypothalamic expression of BDNF through environmental stimuli can induce browning of white adipocytes and increase energy expenditure, but its mechanism is not yet clear (113). Follistatin (FST), as a myocyte factor, can promote the secretion of Irisin in subcutaneous fat through the AMPK-PGC1α-Irisin signaling pathway, inducing WAT browning (35). Myocyte factors can also regulate the lipid metabolism of adipocytes. Studies have shown that IL-15 is lowly expressed in pig adipose tissue and that interleukin-15 (IL-15) regulates lipid accumulation by enhancing lipolysis or inhibiting lipid synthesis through JAK and PKA pathways (36). SPARC, also known as osteonectin or BM-40, is a matricellular protein that belongs to the family of extracellular matrix proteins. It is a cysteine-rich acidic protein and sometimes referred to as an osteogenic protein. SPARC is present in the secretome of various cells, including muscle and bone cells, and is predominantly expressed in subcutaneous adipose tissue. SPARC negatively regulates adipocyte differentiation and adipogenesis in white adipose tissue (WAT) through activation of the Wnt/β-catenin pathway (14). These findings indicate the important role of various myocyte factors in regulating adipocyte browning, thermogenesis, and lipid metabolism.

WAT adipose tissue can secrete a variety of adipokines, such as adiponectin and leptin (19) ( Figure 5 ). Adiponectin activates AMPK in skeletal muscle and stimulates fatty acid oxidation by activating p38 mitogen-activated kinase and PPARa (20). Adiponectin also significantly reduces ceramide levels in exercise-oxidized muscle (15). Leptin promotes skeletal muscle lipid metabolism and fatty acid utilization, as well as energy production to reduce skeletal muscle lipid accumulation (16). Additionally, leptin increases muscle mass by inducing myocyte proliferation factors and negative regulators that inhibit muscle growth, as well as atrophy markers MAFbx and MuRF1 (21). In addition, other adipokines such as retinol-binding protein 4 and endolipin play important roles in regulating the regulation of glucose homeostasis in skeletal muscle as well as insulin uptake (22).

Brown adipose tissue also secretes adipokines, called brown adipokines (BATokines). Overexpression of IRF4 in brown adipocytes decreases serum muscle growth inhibitory hormone and increases muscle motility (12). Thus, IRF4 and muscle growth inhibitor mediate the crosstalk between brown adipose tissue and skeletal muscle. Exercise induces BAT production of 12,13diHOME, which increases skeletal muscle fatty acid uptake and oxidation, and acute 12,13-DHOME treatment in mice exerts the same effect (9). Fibroblast growth factor 21 (FGF21), released by BAT, increases thermogenesis by inducing an increase in BAT and mitochondrial cristae in skeletal muscle under cold exposure conditions (114). In addition, adipocyte-derived exosomes can enter skeletal muscle cells, and exosomal miR-27a induces insulin signaling by inhibiting PPARγ-induced insulin resistance in skeletal muscle (115). Exosomal miR-130b downregulates PGC-1a to reduce mitochondrial oxidative capacity (37). All the above studies have shown that crosstalk between adipose tissue and skeletal muscle is necessary to maintain energy homeostasis ( Figure 5 ).

The gut-brain-BAT axis is a network of information exchange connecting the gut to the brain and to adipose tissue. Studies have shown that factors secreted by the gastrointestinal tract can trigger gut-brain-BAT crosstalk to induce BAT thermogenesis. Glucagon-like peptide 1 (GLP-1) is a peptide hormone secreted by intestinal L cells, and its receptor agonist (GLP-1R) is a new antidiabetic agent in recent years.GLP-1 can regulate white adipose tissue and brown adipose tissue thermogenesis by activating the sympathetic nervous system (38, 116) ( Figure 6 ). The gut hormone glucagon, when released during feeding, triggers gut-brain-brown adipose tissue (BAT) crosstalk to mediate meal thermogenesis, which leads to satiety. Mechanistically, the meal-related elevation of circulating glucagon activates BAT thermogenesis by binding to glucagon receptors in brown adipocytes and promoting lipolysis. This, in turn, sends signals to the brain to produce satiety (117) ( Figure 6 ). The brown fat cells in turn send signals back to the brain to produce a feeling of satiety.

Gut microbiota is closely associated with brown adipose tissue thermogenesis, and white adipose tissue thermogenesis (118) ( Figure 6 ). Studies have shown that alternate-day fasting stimulates white adipose tissue browning and improves obesity and insulin resistance. The mechanism involves a shift in the composition of the intestinal microbiota, resulting in elevated fermentation products acetate and lactate, and upregulation of monocarboxylate transporter protein 1 expression in beige adipocytes (119). The gut microbiota is also able to regulate lipid metabolism in BAT. Deficiency of gut microbiota stimulates hepatic and BAT lipolysis, while inhibiting lipogenesis (120). By transplanting gut microbiota into cold-induced mice, the function of brown adipose tissue in mice could be improved (121). However, In 2019, a study found that depleting the microbiota of mice through antibiotic treatment or asepsis decreased the expression of uncoupling protein 1 (UCP1) and inhibited the browning process of white adipose tissue, resulting in impaired thermogenic capacity of brown adipose tissue. The study found that feeding mice with butyrate, a bacterial metabolite, increased their thermogenic capacity. These findings suggest that the gut microbiota may play a role in upregulating thermogenesis in cold environments, potentially through the action of butyrate (122). The intestinal microorganism E. faecalis and its metabolite myristic acid (MA) have been shown to reduce obesity by activating brown adipose tissue and promoting beige fat formation (123).

Adipose tissue dysfunction is associated with the development of several diseases, and understanding the molecular and cellular mechanisms by which adipose tissue contributes to these diseases will facilitate the development of adipose tissue-based treatments. Adipose tissue has a primary function as a nutrient buffer, protecting other tissues from nutrient toxicity, and in obese patients, the nutrient buffering capacity of adipose tissue fails, leading to systemic toxicity (54). Mutations in genes associated with fat storage and lipolysis can likewise lead to metabolic diseases (124). Obesity leads to adipose tissue overnutrition, and hypertrophy is an adaptive mechanism used by adipose tissue to buffer overnutrition, but hypertrophic adipose tissue over 100 μm in diameter leads to a state of cellular hypoxia, which triggers a cellular stress response, which leads to an inflammatory response from adipocyte apoptosis. Studies have shown that diabetic patients have increased adipocyte hypertrophy in their adipose tissue compared to non-diabetic patients. This indicates a correlation between obesity and diabetes, and further highlights diabetes as a contributing factor in metabolic diseases. Adipose tissue fibrosis restricts adipocyte hypertrophy and has beneficial effects on systemic metabolism. This finding suggests that adipose tissue fibrosis could be a potential target for manipulating adipocyte metabolism (125). When adipocytes reach their hypertrophic limit, lipids spill over into the systemic circulation, leading to tissue toxicity. When visceral adipose tissue reaches its nutrient storage capacity, free fatty acids flood into the liver through the portal system, leading to hepatic steatosis, which progresses to steatohepatitis (126).

The distribution of adipose tissue is heterogeneous and can be divided into subcutaneous and visceral areas. An increased proportion of visceral adipose tissue is associated with an increased risk of metabolic diseases. As we age, subcutaneous adipose tissue shifts to the viscera. The trend of obesity in women is associated with increased expression of lipoprotein lipase in subcutaneous adipose tissue (127). Studies have shown that Fyn knockout mice on normal and high-fat diets have increased glucose clearance and systemic insulin sensitivity, increased fatty acid utilization and energy expenditure resulting in reduced obesity. Analysis shows that Fyn knockout mice shift adipose tissue to the subcutis rather than the viscera, which reduces adipose tissue inflammation associated with T cell and macrophage infiltration (128). The redistribution of adipose tissue by Fyn would serve as a new therapeutic strategy.

The dysfunction of adipose tissue mainly manifests as the disturbance of its metabolic function and the abnormal secretion of hormones. Specifically, it can manifest as dyslipidemia, enhanced inflammatory response, abnormal hormone secretion, and activation of the renin-angiotensin-aldosterone system (RAAS). Adipose tissue dysfunction is closely related to the development of cardiovascular diseases. In obese patients, systemic or local inflammation and insulin resistance can cause macrophages in adipose tissue to switch from anti-inflammatory and anti-atherosclerotic to pro-inflammatory and pro-atherosclerotic. Adipose tissue expansion and dysfunction contribute to the development of cardiovascular disease through direct and indirect mechanisms. It is known that obesity may induce hypertension through visceral adipose tissue expansion causing mechanical compression of the kidney, sympathetic nervous system activity and activation of the renin-angiotensin-aldosterone system (RAAS) (56).