The signaling pathways in obesity‐related complications

Abstract Obesity, a rapidly expanding epidemic worldwide, is known to exacerbate many medical conditions, making it a significant factor in multiple diseases and their associated complications. This threatening epidemic is linked to various harmful conditions such as type 2 diabetes mellitus, hypertension, metabolic dysfunction‐associated steatotic liver disease, polycystic ovary syndrome, cardiovascular diseases (CVDs), dyslipidemia, and cancer. The rise in urbanization and sedentary lifestyles creates an environment that fosters obesity, leading to both psychosocial and medical complications. To identify individuals at risk and ensure timely treatment, it is crucial to have a better understanding of the pathophysiology of obesity and its comorbidities. This comprehensive review highlights the relationship between obesity and obesity‐associated complications, including type 2 diabetes, hypertension, (CVDs), dyslipidemia, polycystic ovary syndrome, metabolic dysfunction‐associated steatotic liver disease, gastrointestinal complications, and obstructive sleep apnea. It also explores the potential mechanisms underlying these associations. A thorough analysis of the interplay between obesity and its associated complications is vital in developing effective therapeutic strategies to combat the exponential increase in global obesity rates and mitigate the deadly consequences of this polygenic condition.

men and 14.9% of women globally.If this trend continues, it is estimated that by 2025, 18% of men and 21% of women will become obese worldwide. 5 interesting meta-analysis of 239 prospective studies, involving 10.6 million individuals from various regions including North America, Asia, and Australia, revealed that the population with a BMI range of 20-25 kg/m 2 had the lowest all-cause mortality rates.
In contrast, overweight and obese populations experienced a significant increase in mortality. 6e increase in adiposity and its connection to numerous complications can be attributed to both structural and metabolic effects.
Subcutaneous adipose tissue primarily functions to store excess calories as triglycerides through adipocyte hypertrophy, which in turn protects vital organs like the liver, heart, and kidneys.However, if the capacity of subcutaneous adipose tissue exceeds a certain threshold, hypertrophied adipocytes can rupture and trigger inflammation, leading to the deposition of triglycerides within visceral adipose tissue. 7The metabolic effects associated with obesity-related complications are primarily caused by the stimulation of proinflammatory cytokines (such as TNF-α, IL-1, IL-6) and lipotoxicity resulting from increased levels of free fatty acids (FFAs) and lipid intermediates like ceramides, which are implicated in insulin resistance, DM, MASLD and CVDs. 8ltiple signaling pathways are involved in the complex pathophysiology of obesity and its related complications.The PI3K/AKT pathway, closely related to insulin signaling is involved in the regulation of various physiological processes and is crucial for maintaining metabolic homeostasis. 9Its function in insulin-sensitive tissues is interconnected with obesity and obesity-related complications.
Moreover, adipose tissue inflammation caused by the activation of mitogen-activated protein kinases (MAPKs) plays a key role in adipogenesis.Additionally, MAPKs cause glucose intolerance in obese states by directly inactivating IRS1 and indirectly inactivating PPARγ.Furthermore, the JAK-STAT pathway participates in leptin -mediated anorectic effects and regulates fat accumulation in the liver.Finally, other signaling mechanisms include the AMPK pathway, whose activation causes weight gain, TGF-β signaling involved in the regulation of glucose homeostasis and endoplasmic reticulum (ER) signaling pathways in which the accumulation of unfolded protein response in the ER causes metabolic dysfunction. 10is narrative review aims to summarize the major pathophysiological connections between obesity and its complications, by analyzing the pathways and key features of the signaling mechanisms that underlie this association.

| SIGNALING PATHWAYS INVOLVED IN THE PATHOPHYSIOLOGY OF OBESITY-ASSOCIATED COMPLICATIONS
An in-depth knowledge of the signaling pathways involved in obesityassociated complications is crucial for gaining a better understanding of the mechanistic insights needed for targeted therapeutic approaches.However, there are direct and indirect effects that impact an individual's susceptibility to obesity, which results from excessive calorie consumption and/or insufficient calorie expenditure.Unfortunately, the underlying metabolic processes are influenced by numerous signaling pathways that can either promote or counteract obesity (Figure 1).
In the following, we will discuss some of the important signaling cascades.

| Mitogen-activated protein kinase pathways
Several studies have shown that the three tiered cascade of (MAPKs) is essential for signal transduction.The MAPKs ERK1/2, c-Jun Nterminal kinase (Jun N-terminal kinase (JNK)) and p38, play crucial roles in regulating adipogenesis, glucose homeostasis, and thermogenesis. 11Specifically, the activation of MAPK stimulates adipose inflammation in obesity.This was demonstrated in a study showing that inhibiting the caspase recruitment domain 9/MAPK pathway led to reduced inflammation, improved glucose tolerance, and decreased adipocyte enlargement. 12CARD9 is an adapter protein associated with immune cell activation and inflammatory responses.Previous studies have shown that CARD9 overexpression activates the kinases p38 and JNK, which are essential for producing proinflammatory cytokines. 13The study by Zeng et al. further found that Card9 −/− mice had lower mRNA expression of p38 MAPK, JNK and ERK compared to wild-type mice. 12Another study used multiomics analysis in mice fed a high-fat diet and showed that inflammatory genes are enriched in the ERK MAPK pathway, particularly in macrophages. 14MAPKs also plays a vital role in causing insulin resistance by directly inactivating insulin receptor (INSR) substrate (IRS)-1 and indirectly activating PPAR-γ. 15,16The phosphorylation of PPARγ by ERK enhances the ability of transcriptional coactivator with PD2binding motif to negatively regulate PPARγ, causing impaired insulin sensitivity.The p38 MAPK pathway maintains glucose homeostasis in obesity by enhancing mRNA stability and nuclear migration of X-box binding protein in the liver. 17Under obese conditions, chronic inflammation leads to insulin resistance in adipose tissue.
p38α functions as a central mediator of β-adrenergic induced uncoupling protein 1 expression in brown adipocytes.In white adipocytes, inactivation of p38α leads to increased reprogramming from white to beige adipocytes and resistance to diet-induced obesity. 18,198α controls lipolysis and protects against fatty liver in hepatocytes. 20This was evidenced by the development of severe steatohepatitis in high fat diet fed liver specific p38α knockout mice. 20cochalcone F, a synthetic retrochalcone, was found to inhibit TNFα-induced expression of inflammatory factors, reduce adipocyte size, decrease macrophage infiltration in white adipose tissue, and alleviate glucose intolerance by interacting with MAPK signaling pathways. 21It has been shown that Licochalcone F enhances AKT signaling and reduces p38 MAPK signaling in white adipose tissue.
The anti-inflammatory effects of Licochalcone F in alleviating obesity-induced chronic inflammation are partially attributed to its 2 of 20 -JOURNAL OF CELL COMMUNICATION AND SIGNALING ability to downregulate the p38 signaling pathway.In the central nervous system, ERK1/2 regulates appetite by enhancing glucosestimulated proopiomelanocortin (POMC) gene expression in hypothalamic neurons. 22Additionally, it has been demonstrated that leptin is modulated by JNK3 in high-fat diet fed mice, specifically on Agrp neurons. 11rthermore, MAPKs play crucial roles in the complex interaction between obesity and insulin resistance.The dual-specificity phosphatase 9 (DUSP9), a cytoplasmic phosphatase, is known to dephosphorylate ERK1/2, JNK and ASK1 thereby controlling various MAPK pathway cascades.The dephosphorylation of multiple MAPKs such as ERK1/2, JNK, p38 and ASK1 kinases by DUSP9, restores the tyrosine phosphorylation of IRS1 alleviating glucose intolerance. 23terestingly, JNK1 and JNK3 stimulate the serine/threonine phosphorylation of IRS1 and IRS2, which in turn induces insulin resistance. 24In brown adipose tissue (BAT), IL-27, as well as the p38 MAPK/PGC-1α signaling pathway, play a fundamental role in promoting adipocyte thermogenesis and energy expenditure. 14,25

| The interconnection between JAK/STAT signaling pathway and obesity
The JAK/STAT signaling pathway is a crucial signal transduction pathway comprised of JAK1, JAK2, and JAK3, along with STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6.This pathway plays a direct role in obesity and interacts with MAPK or PI3K. 26e binding of cytokines and growth factors to their corresponding receptors leads to receptor dimerization and recruitment of related JAKs.Subsequently, the ligand-receptor connection induces transphosphorylation of JAK.The activated JAK causes receptor tyrosine phosphorylation, forming a docking site for STATs.
JAK phosphorylates STAT at the docking site, leading to the dissociation of STAT from the receptor to form heterodimers or homodimers through SH2-domain phosphotyrosine interactions.The translocation of these dimers targets the gene promoters and regulates the transcription of target genes.STAT either binds to its DNA target site or forms a complex with non-STAT transcription factors to regulate transcription.The non-classical JAK/STAT signaling involves unphosphorylated STAT3 inducing multiple STAT3 target gene expressions without Ser727 phosphorylation and Lys685 acetylation. 27e positive regulators of JAK/STAT signaling include the formation of a glucocorticoid receptor complex with activated STAT5.This complex promotes STAT5-dependent transcription.Additionally, the transcriptional coactivator CBP/p300 and p30 acts as auxiliary activators of STAT1α.N-myc-interactor (Nmi), a cytoplasmic protein, enhances STAT1 and STAT5 activation by recruiting them through CBP.The SH2 protein subfamily, which includes the isoforms lymphocyte adapter protein (LnK), SH2-B, and adapter molecule containing PH and SH2 domains (APS), serves as adapters in the signaling pathway.SH2-B facilitates glucocorticoid hormone-induced JAK2 activation, while APS functions as a negative regulator of JAK/ STAT signaling.Other negative regulators include the suppressors of The complexity and interconnected nature of crucial signaling pathways that mediate signals either promoting or counteracting obesity.There are numerous pathways involved in promoting or counteracting obesity, which impact appetite, thermogenesis, lipolysis, adipose tissue metabolism, glucose and fat homeostasis, adipogenesis, and energy expenditure.Key pathways include MAPKs, PI3K/AKT, JAK/ STAT, TGF-β, AMPK, and Wnt/β-catenin.These pathways are interconnected and can have both stimulating and inhibiting effects.For example, the AMPK pathway directly affects lipolysis while also promoting insulin resistance and inflammation in adipose tissue.Another example is the JAK/STAT pathway, which has anti-obesity effects by impacting thermogenesis, lipolysis, and hypophagia, while also promoting the pathogenesis of obesity by impacting adipose tissue inflammation and insulin resistance.The various activities and interconnection of the pathways depicted make it highly difficult to develop suitable drugs.This figure has been redrawn in a modified form from the work of Wen and colleagues. 10ytokine signaling/cytokine-inducible SH2 protein (CIS) family, protein inhibitor of activated STAT and protein tyrosine phosphatases.28 Leptin is a hormone that acts on the hypothalamus to regulate food intake and energy expenditure.The ob/ob mice lacking leptin or the db/db mice lacking the leptin receptor, develop severe obesity and insulin resistance. 29en leptin binds to the β-isoform of the leptin receptor, it activates JAK2 through auto-phosphorylation.This process phosphorylates tyrosine residues on the cytoplasmic tail of the receptors, such as Y985, X1077 and Y1138, enabling the recruitment and phosphorylation of signaling molecules STAT3 and STAT5.The activation of STAT3 increases the expression of genes encoding proopiomelanocortin (POMC) and inhibits the expression of Agouti-related peptide (AgRP) and neuropeptide Y (NPY) in the neurons of the hypothalamic arcuate nucleus.The POMC and AgRP/ NPY peptides have opposite functions and mediate anorectic responses to leptin, promoting changes in satiety.22 The targeted knockout of STAT3 in neural tissue, including the hypothalamus, leads to obesity that closely resembles the phenotype of ob/ob or db/db mice.30 Deleting STAT5 in the brains of mice also results in obesity, primarily due to increased food intake, indicating that STAT5 activation is crucial for satiety in the central nervous system.31 However, the specific STAT5 target genes responsible for this effect have not yet been identified.31 Mutations in genes such as those encoding the SH2-B adapter protein have been linked to aberrant JAK/STAT signaling in the central nervous system, contributing to the development of obesity.32,33 In the liver, hepatic steatosis is partially regulated by the JAK/ STAT signaling mechanism, which is influenced by cytokines and growth factors.Growth hormone, secreted by somatotropic cells in the anterior pituitary gland, plays a critical role in regulating the production of hepatic insulin-like growth factor 1 (IGF-1) through activation of JAK2 and STAT5. Abrrations in the IGF/growth hormone axis have been implicated in obesity development in rodents and humans.34 It is hypothesized that low levels of growth hormone cause decreased lipolysis and fatty acid oxidation in adipose tissue, leading to increased hepatic steatosis.35 Liver-specific deletion of STAT5 in mice results in obesity and glucose intolerance.The absence of STAT5 in the liver increases the phosphorylation of STAT1 and expression of its target genes, including CD36, PPAR-γ, and PGC-1α/β, respectively, leading to increased lipogenesis, fatty acid uptake, and steatosis.This suggests that loss of STAT5 induces the expression of CD36, PPARγ, and PGC1α/β.36 Several studies have emphasized the importance of STAT3 in liver function.Liverspecific deficiency of STAT3 has been shown to cause insulin resistance and increased expression of gluconeogenic genes.Conversely, activation of STAT3 in liver cells has been found to prevent hepatic lipid accumulation.37

| Obesity and the PI3K/AKT pathway
The PI3K/AKT pathway is activated by various upstream signals, such as hormones and growth factors, which contribute to obesity.Upon activation, PI3K converts phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3), subsequently activating AKT.AKT then regulates glycogen synthase kinase 3, protein kinase C and the Forkhead-box (FOX) protein family to control glycogen synthesis, glucose uptake, and adipogenesis.The primary targets of the PI3K/AKT pathway, including the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and mTORC2 also play a significant role in the development of obesity. 38search has shown that leptin suppresses food intake partly through the PI3K/AKT/FOXO1 pathway.Inhibition of PI3K specifically reduces the effects of leptin, highlighting the importance of PI3K/AKT in appetite regulation.Additionally, the PI3K/AKT/mTOR signaling pathway has dual effects on thermogenesis and negatively regulates food intake. 39One of the most notable impacts of the PI3K/AKT pathway is its role in insulin signaling.Impairment of PI3K/ AKT signaling leads to the degradation of sortilin 1 (SORT1), a component of glucose transporter 4 (GLUT4) storage vesicles, and decreases insulin sensitivity. 40In the liver, the PI3K/AKT/mTOR and PI3/AKT/FOXO1 pathways contribute to de novo lipogenesis and hepatic glucose production. 41,42flammation of adipose tissue is a key factor in insulin resistance.The infiltration and accumulation of CD4 þ T cells are primary events that play a crucial role in initiating adipose tissue inflammation.Recently, it was discovered that Kruppel-like-zinc finger family 10 (KLF10) in CD4 þ T cells plays a crucial role in obesity and insulin resistance.These effects are mainly mediated by the PI3K-AKT-mTOR signaling pathway. 43

| The role of AMPK pathway in obesity
Recent evidence has illuminated the AMP-activated protein kinase (AMPK) pathway and its involvement in obesity, insulin resistance, and BAT thermogenesis.In the central nervous system, activation of AMPK contributes to weight gain, and AMPK plays a role in a feedback system that regulates feeding mechanisms.Consequently, fasting boosts AMPK activity in the hypothalamus, while refeeding suppresses its activity. 44It is therefore proposed that AMPK levels in adipose tissue are diminished in individuals with insulin resistance, aligning with the finding that mice with an adipocyte-specific disruption of AMPK are more susceptible to developing insulin resistance and related conditions. 45The activation of AMPK in adipocytes inhibits adipogenesis, enhances insulin sensitivity, promotes thermogenesis, and leads to weight loss.However, in the central nervous system, AMPK activation results in insulin resistance, reduced thermogenesis, weight gain, and increased appetite.

| Obesity and TGF-β signaling: An overview
The TGF-β superfamily, which includes TGF-β1, TGF-β2, TGF-β3, bone morphogenetic proteins and growth/differentiation factors plays a versatile role in the development of obesity.The pro-fibrotic, remodeling and pro-inflammatory functions of TGF-β mechanistically link to many comorbidities associated with obesity.The TGF-β family comprises 33 structurally and functionally related growth factors.TGF-β1 signals downstream through SMADdependent and SMAD-independent pathways and acts through a heteromeric receptor complex comprising type 1 and type 2 receptors. 46,47The cellular effects of TGF-β are mediated by receptoractivated SMADs (R-SMADs).The phosphorylated type 1 receptor phosphorylates the SMAD protein targets with SMAD two-thirds forming a complex with SMAD4, translocating into the nucleus to regulate gene expression.The SMAD2/3/4 complex is considered a co-activator, interacting with CBP and p300 to enhance gene expression.In parallel, the SMAD complex interacts with chromatin remodeling complexes in the nucleus to regulate the active chromatin status.SMADs 6 and 7 are the inhibitory SMADs that inhibit SMAD2 and SMAD3 phosphorylation to attenuate complex formation with SMAD4 for transcriptional activity in the nucleus. 48F-β1 signaling plays a crucial role in regulating energy homeostasis, insulin resistance and phenotypic switching in BAT and white adipose tissue.It has been demonstrated that obesity increases hepatic TGF-β1 activity along with markers of inflammation. 49In animal models of obesity induced by a high-fat diet, TGF-β and plasminogen activator inhibitor-1 (PAI-1) mRNA levels were increased in adipose tissue.In murine models of obesity, TGFβ was shown to increase CD206 þ M2-like macrophages in white adipose tissue that are linked to decreased white adipose tissue browning in insulin resistance. 50In summary, TGF-β contributes to dysfunctional adipose tissue in obesity with impaired adipogenesis and amplified inflammation and fibrosis.TGF-β induced adipose tissue progenitor cells to increase the expression of collagen and IL-6 thereby promoting pro-fibrotic and inflammatory phenotypes.TGF-β1 also signals through SMAD-independent pathways such as MAPKs, PI3K/ AKT and Ras-related C3 botulinium toxin substrate (RAC)/cell division cycle 42 (CDC42). 51e important member of the TGF-β superfamily, GDF-15, has been identified as a crucial regulator of appetite.It has been reported that mice lacking GDF-15 exhibit increased adiposity.Another member, BMP-4, and its antagonist Gremlin, are known to promote white adipose tissue browning, thereby reducing adiposity. 52,53F-β signaling is also involved in the regulation of glucose tolerance.Blocking of TGF-β/SMAD3 signaling has been shown to have protective effects on mice, preventing obesity, insulin resistance, and hepatic steatosis.This protection is achieved through the activation of PPARγ in adipose tissue. 54

| Endoplasmic reticulum signaling pathways and obesity
Recently, there has been an increased focus on obesity-induced ER stress, where unfolded proteins accumulate in the ER, causing stress and metabolic dysfunction.In conditions of ER stress, a protein called mesencephalic astrocyte-derived neurotrophic factor (MANF) is released in large amounts and activates the unfolded protein response signaling pathway, while also negatively regulating NF-κB signaling. 55NF-κB is an inducible factor that has a low constitutive expression but can be strongly induced by a various factors.It acts as a general stress sensor, inducing gene-regulatory mechanisms, and fine-tuning mRNA and protein expression of specific sets of genes. 56NF in the hypothalamic regions leads to increased appetite and adiposity by inducing the expression of phosphatidylinositol-5phosphate 4-kinase type 2 beta (PIP4K2b), which triggers insulin resistance and ultimately results in the accumulation of fat mass. 55few studies have shown that mice with liver-specific knockout of MANF demonstrate impaired browning of white adipose tissue and exaggerated obesity.However, liver-specific overexpression of MANF protects these mice against diet-induced obesity by enhancing WAT browning.57 IRE1α, an ER stress sensor activated by nutrients, hormones, and immunological triggers, leads to increased IL-1β secretion.Other inflammatory triggers such as lipopolysaccharides and IL-4, activate splicing of IRE1α through interactions with toll-like receptors.58

| High blood pressure and obesity
The risk of developing CVDs is significantly higher in hypertensive obese individuals compared to non-obese individuals.It has been identified that 85% of high blood pressure occurs in patients with a BMI greater than 25 kg/m 2 . 59According to the guidelines of the American Heart Association, hypertension is defined as systolic blood pressure ≥130 mmHg and diastolic blood pressure ≥80 mmHg. 60e relationship between obesity and hypertension can be explained by several mechanisms, including enhanced renal absorption of sodium, activation of the renin-angiotensin aldosterone system (RAAS) and sympathetic nervous system (SNS), release of angiotensin from adipose tissue and insulin resistance. 61The overactivity of the SNS manifests as an increase in heart rate, elevated cardiac output and renal tubular sodium reabsorption as a direct effect of α and β adrenergic activation. 62It is important to note that this SNS activation is exaggerated even with slight weight gain.The activation of the SNS in obesity is a consequence of abnormal adipokine secretion from adipose tissue, insulin resistance, and stimulation via RAAS. 63Moreover, the sympathetic tone due to excess adiposity is influenced by a multitude of factors, such as visceral fat accumulation, ethnicity, and sex differences.The overactivation of the SNS predominantly affects the kidneys and skeletal muscles. 63e activation of RAAS leads to higher levels of plasma renin.
Angiotensin, produced by the RAAS, induces systemic vasoconstriction and stimulates the production of aldosterone from the adrenal cortex.This results in increased tubular sodium reabsorption and water retention, consequently leading to hypertension. 64The activation of RAAS in obesity is attributed to a reciprocal interaction between the sympathetic-adrenal system and RAAS.Both systems activate each other and drive the upregulation of renin from juxtaglomerular cells.Additionally, excess lipid accumulation causes JOURNAL OF CELL COMMUNICATION AND SIGNALING kidney compression, increasing renin secretion, and excess adipocytes increase angiotensin II production. 65One of the notable structural and functional renal changes associated with obesityinduced hypertension is the accumulation of perirenal fat.This accumulation induces inflammation and expansion of the renal medullary extracellular matrix, compressing the renal medulla. 66The resulting decrease in renal tubular blood flow causes a decrease in sodium delivery to the Macula densa distally, stimulating a feedbackmediated reduction in renin secretion.However, the elevated glomerular hydrostatic pressure impairs renal function, exacerbating sodium retention and increasing arterial pressure to maintain sodium delivery to the macula densa.Moreover, insulin resistance in obese states contributes to increased blood pressure by directly promoting renal sodium retention in the proximal convoluted tubule through the activation of the sodium-hydrogen exchanger 3 (NHE3), also known as solute carrier family 9, member 3 (SLC9A3).In obese individuals with chronic hyperinsulinemia, endothelial dysfunction results in vasoconstrictor tone. 59 is interesting to note that leptin levels are high in the obese population, indicating a state of leptin resistance.The high levels of leptin contribute to obesity-induced hypertension through SNS activation. 67The treatment of hypertension in obese adults is primarily based on calorie restriction and maintaining a healthy BMI.
Although multiple hypertensive medications are available, it is ideal to prefer medications such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and calcium channel blockers that do not stimulate insulin resistance rather than insulin resistance-enhancing drugs such as thiazide diuretics and βblockers. 68

| Obesity and dyslipidemia
The unfavorable shift and changes in the lipid profile of obese individuals include an increase in triglycerides and FFAs, a decrease in HDL, and an increase in LDL.These changes, along with insulin resistance, create a highly atherogenic environment and postprandial hyperlipidemia. 69Additionally, there is a shift in lipid metabolism towards the creation of small dense LDL particles. 70Obesity, metabolic syndrome, and dyslipidemia are linked by insulin resistance in peripheral tissues, which leads to an increased hepatic flux of fatty acids from lipolysis and from adipose tissue that is resistant to the anti-lipolytic effects of insulin. 71,72e hallmark feature of hypertriglyceridemia, due to increased FFA fluxes leads to hepatic accumulation of triglycerides.This, in turn, increases hepatic synthesis of VLDL hampering the lipolysis of chylomicrons and resulting in increased remnant triglycerides transported to the liver.The reduced activity of lipoprotein lipase in adipose tissue and skeletal muscle further impairs lipolysis. 73The increase in chylomicron levels and VLDL levels together with impaired lipolysis affects HDL metabolism.These dyslipidemic features in obese individuals, along with a pro-inflammatory gradient, directly affect the endothelium.It is well known that elevated plasma FFA levels are a consequence of FFA release from adipose tissue and impaired clearance of these FFAs.
Together with obesity-induced inflammation, they play a critical role in the development of insulin resistance.Cytotoxic FFAs such as saturated fatty acids, arachidonic acid, and linoleic acids, mediate diet-induced inflammation, stimulating the synthesis of proinflammatory cytokines such as IL-1, IL-6 and TNF-α. 74It is interesting to note that small dense LDL particles are more proatherogenic than large LDL particles due to their decreased affinity to the LDL receptor, causing prolonged circulation time.Strikingly, these particles can enter the arterial wall more easily than large LDL particles and get trapped in the arterial wall by binding to intraarterial proteoglycans.In addition, the small dense LDL particles are more prone to oxidation, resulting in enhanced uptake by macrophages. 75Another source of increased fatty acid delivery to the liver is the increase in adipose tissue mass and the increase in fatty acid synthesis by insulin-stimulated activation of the sterol regulatory element-binding protein 1c (SREBP1c), a transcription factor that increases the expression of genes involved in fatty acid synthesis. 76 cases of insulin resistance in obese individuals, abnormalities in triglyceride lipoprotein metabolism, such as an increase in apolipoprotein C-III (APOC3) expression, lead to reduced clearance of triglyceride-rich lipoproteins.APOC3 acts as an inhibitor of lipoprotein lipase (LPL). 77Additionally, circulating levels of adiponectin are decreased in obese individuals, resulting in higher serum triglycerides.This is further supported by a study in mice that showed a decrease in triglycerides and an increase in HDL cholesterol in those that overexpressed adiponectin. 78e multifactorial pathophysiology of dyslipidemia in obesity includes hepatic overproduction of VLDL, decreased triglyceride lipolysis, impaired peripheral FFA clearance, increased FFA fluxes from adipose tissue to the liver, and the formation of small dense LDL particles.A combination of dietary and lifestyle modifications, such as exercise, has proven beneficial in managing dyslipidemia in obese populations.Weight loss alone has been shown to be effective in decreasing LDL levels and increasing lipoprotein lipase activity.
Pharmacological interventions for dyslipidemia primarily involve the use of statins, which are the popular first line of therapy due to their favorable effects on LDL profiles.However, statins have been found to have little effect on triglyceride levels in dyslipidemic obese individuals. 79Recently, bariatric surgery-induced weight loss has gained popularity and has been associated with increased HDL cholesterol, decreased triglyceride levels, and is a therapeutic option if the combination of lifestyle modifications and pharmacotherapy fails. 80,81 increase in the release of FFAs from adipose tissue through lipolysis can result in an enhanced delivery of FFAs to the liver.This, in turn, leads to an increased production of triglycerides and VLDL in the liver, as well as the inhibition of lipoprotein lipase in adipose tissue and skeletal muscle.These factors contribute to hypertriglyceridemia. Additionally, the increased VLDL in the liver can hinder the lipolysis of chylomicrons, further exacerbating hypertriglyceridemia.The cholesteryl ester transport protein exchanges triglycerides and VLDL for cholesteryl esters from LDL and HDL, creating triglyceride-rich LDL and HDL.Hepatic lipase then hydrolyzes the triglycerides in LDL and HDL, resulting in the production of small, dense LDL and HDL.

| MASLD and obesity
The accumulation of fat in the liver, known as intrahepatic lipid accumulation, is primarily caused by elevated levels of FFAs, resulting from an increased BMI.In the case of insulin resistance, the rise in FFA production and intrahepatic lipid accumulation occurs because carbohydrate metabolism shifts away from intramuscular glycogen stores and towards the liver. 82Together these effects can result in metabolic dysfunction-associated liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). 83Another connection between MASLD and increased BMI is the heightened expression of hepatic lipase and lipoprotein lipase, which enhances triglyceride metabolism within the liver. 84The combination of elevated circulating FFAs and increased intrahepatic triglyceride metabolism contributes to the development and progression of hepatic steatosis.The association between obesity and a constellation of liver abnormalities, characterized by increased hepatic fatty acid uptake and de novo lipogenesis, is mainly characterized by abnormalities in glucose, fatty acids, lipoprotein metabolism and inflammation, leading to increased levels of intrahepatic triglycerides. 85In parallel, the alterations in fatty acid transport promote the accumulation of ectopic lipids in the liver of individuals with insulin resistance, leading to an increase in intrahepatic triglyceride content and redirection of plasma FFAs from adipose tissue to other tissues.This is supported by the finding that the expression of CD36, which regulates tissue fatty acid uptake from plasma, is decreased in adipose tissue and increased in the liver and skeletal muscle of obese individuals with insulin resistance. 86ring de novo lipogenesis carbohydrates are converted to fatty acids.In this process several enzymes are important and are primarily regulated at the transcriptional level. 87These enzyme accounts for less than 5% of the fatty acids incorporated into secreted very lowdensity lipoprotein triglycerides.However, in MASLD, the contribution of de novo lipogenesis to total intrahepatic glucose production is much higher, accounting for 15%-23% of fatty acids secreted in very low-density lipoprotein triglycerides. 88This suggests that in obese individuals with insulin resistance, the rate of de novo lipogenesis may have important regulatory functions.Intrahepatocellular fatty acid oxidation primarily occurs within the mitochondria, and the inhibition or activation of this oxidation can influence lipid accumulation and triglyceride content in the liver.Mitochondrial dysfunction and deficiencies in mitochondrial enzymes lead to hepatic steatosis. 89llectively, the interrelationship between steatosis and increased BMI is due to various factors, such as an increased rate of FFA uptake by the liver, increased intrahepatic de novo lipogenesis of fatty acids, increased production and secretion of triglycerides in VLDL, and inhibition of fatty acid oxidation by high plasma glucose, which affects SREBP1 and carbohydrate-responsive element-binding protein (ChREBP).It is critical to manage MASLD with weight loss and treat contributing conditions, such as DM, before it progresses to cirrhosis, which can cause irreversible damage to the liver.Figure 2 provides a summary of the interactions between increased adiposity and MASLD.

| Obesity and gastrointestinal complications
Obesity-related gastrointestinal complications include gastroesophageal reflux disease (GERD), hepatocellular carcinoma, cholangiocarcinoma, pancreatic cancer, Barrett's esophagus, gallstones, and esophageal cancers. 90These gastrointestinal conditions are attributed to insulin resistance, which is caused by increased levels of FFAs, leptin, TNF-α, resistin, and a decrease in adiponectin.As a result, there is an increase in insulin-like growth factor-binding protein 1 and IGFBP2 levels in obese individuals with insulin resistance.This leads to an increase in IGF-1 bioavailability, which promotes cell proliferation in target cells and inhibits apoptosis.The activation of the IGF receptor signaling pathway caused by increased IGF-1 further contributes to the development of cancers.Cell proliferation is induced through the activation of PI3K and AKT/PKB, as well as mTOR and RAS/RAF/MAPK pathways. 91iponectin is an antidiabetic, insulin sensitizer with antiinflammatory properties.It inhibits cell proliferation and induces apoptosis through various pathways such as adiponectin receptor (adipoR) 1-and adipoR2-mediated AMPK activation.It also increases expression of AKT and ERK signaling pathways in pancreatic β-cells and lung epithelial cells.Circulating adiponectin has an inverse relationship with BMI, 92 which leads to an increased risk of gastrointestinal cancers in obese individuals due to decreased adiponectin levels.
Multiple studies have shown that obesity is a significant risk factor for GERD. 93Abdominal visceral obesity is closely associated with GERD compared to BMI.This is due to lower esophageal sphincter abnormalities, an increased risk of hiatal hernia, and increased intragastric pressure.The increase in intra-abdominal pressure causes reflux of gastric contents within the esophageal body, while altered post-esophageal pressure gradient causes retrograde flow of gastric contents. 94In addition, abnormalities in adiponectin and leptin secretion are proposed to link obesity and GERD by modulating gastrointestinal motility both centrally and peripherally.
In the obese population, symptoms of functional dyspepsia, such as bloating, vomiting, nausea and discomfort, are caused by gastric motor dysfunction, impaired gastric emptying, and gastric motility. 95e risk of gallbladder disease also increases with obesity.A systematic review of 17 prospective studies involving 1,192,103 participants showed a 2-fold increase in gallbladder disease in obese individuals. 96Gallbladder dysmotility and increased leptin levels due to abdominal obesity and insulin resistance are the suggested JOURNAL OF CELL COMMUNICATION AND SIGNALING mechanisms to explain the relationship between obesity and gallbladder dysfunction. 97While weight reduction alone is not a robust treatment for GERD, modest weight loss could help alleviate GERD symptoms.Other management strategies include symptomatic treatment along with weight loss strategies.The gastrointestinal and hepatobiliary complications associated with obesity are depicted in Figure 3.

| Obstructive sleep apnea
OSA is a common condition in obese individuals, characterized by excessive daytime sleepiness and an increased risk of CVD.The proposed mechanisms linking obesity and OSA include an increase in upper airway adiposity, elevated levels of adipokines, and an enlarged neck circumference. 98It is characterized by the collapse of the upper airways during sleep, resulting in intermittent hypoxia and sleep disruption.This condition is associated with an increased risk of cardiovascular problems.Typically, OSA patients are overweight or obese and often have other conditions such as hypertension, type 2 DM, or dyslipidemia. 99The linear correlation between obesity and OSA can be explained by a decrease in muscle activity in the upper respiratory tract due to fat deposits.This leads to a narrowing of the airway, hypoxic episodes, and sleep apnea.These hypoxic episodes result in a decrease in oxygen availability to body tissues and blood vessels contributing to a high risk of CVD. 100 Obese individuals often experience short sleep duration, which can lead to hormonal imbalances.For instance, a lack of sleep can decrease melatonin levels, disrupting the metabolic circadian rhythm and increasing the risk of metabolic syndrome. 101In addition, altered levels of leptin and insulin can increase food craving and contribute to excessive calorie intake, further raising the risk of DM and other complications associated with metabolic syndrome.
In the case of OSA, episodes of apnea or hypoxia can trigger increased sympathetic activation and cause a drop in oxyhemoglobin saturation from 95% to 80%.It is important to note that hypoxia can lead to oxidative stress, resulting in the overproduction of reactive oxygen species (ROS).This can lead to endothelial dysfunction and ultimately contribute to the development of atherosclerosis. 102Making dietary modifications and increasing physical activity can be effective strategies for weight loss and alleviating symptoms of moderate OSA.Continuous positive airway pressure is the standard treatment for this disease and can improve the functional status of individuals with this condition.It is crucial to take a multi-targeted approach to address obesity and manage OSA in order to reduce the risk of CVD in this population.Figure 4 provides a visual representation of the relationship between obesity and OSA.

F I G U R E 2
Pathogenetic events leading to metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunctionassociated liver disease (MASLD).Expansion and low-grade inflammation of adipose tissue are hallmarks of obesity, which result in dysfunction in adipocytes, insulin resistance, and increased rates of lipolysis.Additionally, adipose tissue secretes high levels of cytokines (specifically interleukins), adipokines, leptins, and free fatty acids, while the expression of adiponectin, a factor that regulates glucose levels, decreases.As a result, hepatic de novo lipogenesis is stimulated, leading to the accumulation of fat in the liver and lipotoxicity.This, in combination with chronic glucotoxicity, triggers endoplasmic reticulum stress, oxidative stress, mitochondrial defects, cell death, and apoptosis.In liver tissue, quiescent hepatic stellate cells become activated and produce large amounts of extracellular matrix compounds, ultimately resulting in fibrosis and cirrhosis.

| Polycystic ovary syndrome and obesity: A pathophysiological view
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder, affecting around 7% of women in the reproductive age group.It is characterized by increased production of androgens and abnormal levels of gonadotropin hormones.This leads to anovulation, infertility or impaired fertility, menstrual irregularities, acne, and androgenic alopecia.Strikingly, the PCOS population often demonstrates insulin resistance and hirsutism.PCOS is also associated with impaired glucose tolerance, MASLD, dyslipidemia, and OSA.The increased adiposity in PCOS has deleterious effects on hormonal levels, specifically increasing testosterone levels.This leads to central obesity, visceral fat distribution, and the interplay of obesity and hormonal levels negatively impacting fertility. 103It is alarming to note that 40%-80% of PCOS patients are obese. 104OS is closely related to insulin resistance, and it is proposed that testosterone and the CAG repeat number within the androgen receptor contribute to the development of insulin resistance.The post-receptor defect specific to the PI3K pathways and the stimulating effects on intact MAP kinase pathway by compensatory hyperinsulinemia enhance steroidogenesis. 103The adverse effects of hyperinsulinemia on preantral follicular development cause ovulatory dysfunction.Rodent models show the development of hyperandrogenemia with enhancement of luteinizing hormone (LH) pulse amplitude in the pituitary and stimulation of adrenal cytochrome P450C17α activity. 104The effects of hyperinsulinemia in insulin resistance drive enhanced steroidogenesis within the ovary and F I G U R E 3 Gastrointestinal and hepatobiliary complications associated with obesity.Excess body weight and obesity are risk factors for various gastrointestinal and hepatobiliary malignancies that can affect the esophagus, stomach, colon, small intestine, anorectum, liver, gallbladder, and pancreas.The symptoms and conditions related to the gastrointestinal system are wide-ranging.This figure has been modified and expanded from the original work by Camilleri and colleagues. 97irect effects within the adrenal resulting in hyperandrogenic features. 103ipocytes in women with PCOS exhibit abnormal lipolytic function.Androgens have a stimulatory effect on lipolysis in these adipocytes, leading to impaired adipocyte differentiation, insulin signaling, and adipokines.Therefore, androgen-mediated enhanced visceral lipolysis is a significant mechanism involved in PCOS. 105creased fat mass amplifies LH stimulation by enhancing the sensitivity of thecal cells, resulting in increased ovarian androgen production.Given the close relationship between PCOS and insulin resistance, it is crucial to understand the underlying mechanism of insulin resistance in PCOS.Visceral fat accumulation plays an essential role in contributing to insulin resistance in PCOS through the effects of adipokines and fatty acid release. 106Thus, in addition to its association with the pleotropic steroidogenic effects of excessive insulin through the intact MAPK post-receptor insulin pathway and impaired PI3K pathway, the core component of PCOS pathogenesis is linked to insulin resistance in obese women.Compensatory hyperinsulinemia also plays an important role in the pathophysiology of the pituitaryovarian axis.The management of PCOS revolves around weight loss and the treatment of insulin resistance and anovulation. 105ven the complexity of PCOS pathogenesis, it is important to consider the effects of PCOS on further weight gain and hindering weight loss efforts. 107As mentioned earlier, PCOS is responsible for abnormalities in the lipolytic functioning of adipocytes.One study demonstrated that catecholamine induced lipolysis was increased twofold within the isolated visceral adipocytes in non-obese women with PCOS compared with BMI-matched control women.This increase was possibly mediated by changes in the function of the postreceptor protein kinase A-hormone-sensitive lipase complex. 108though the effects of androgens on adipocytes cause stimulation of lipolysis, impaired adipocyte differentiation, insulin signaling and generation of adipokines, there is tight control of exposure of adipocytes to androgens through key isoenzymes.Thus, the effects of androgens on adipocyte function and lipolysis in PCOS women are incompletely understood and further research is needed. 109I G U R E 4 Relationship between obesity and obstructive sleep apnea (OSA) syndrome.Dysfunction of the adipose tissue, gut, and respiratory system are closely related in obesity-induced OSA.Accumulated fat produces low-grade inflammation, lipolysis, oxidative stress, hyperglycemia, leptin and insulin resistance, as well as significant pro-inflammatory mediator production.In parallel, the composition of the gut microbiota is altered, leading to increased gut permeability and release of endotoxins such as lipopolysaccharides (LPS) that affect the adipose tissue and the respiratory system.Moreover, short-chain fatty acids (SCFAs) generated from the gut microbiota can significantly contribute to the development of metabolic disorders.Overweight further reduces respiratory muscle strength, leading to intermittent hypoxia that further triggers inflammation, oxidative stress, vascular function, and provokes neuro-humoral changes.Additional information about the relationship between obesity and obstructive sleep apnea and the adverse effects on other tissues are discussed in detail elsewhere. 100 of 20 -

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In addition to features like hirsutism, menstrual irregularities and fertility problems, women with PCOS are also susceptible to mental health problems.This provides a reasonable explanation for the potential hindrance to successful weight loss measures in PCOS women with anxiety and depression.In summary, a vicious cycle may result in worsening PCOS features and weight gain due to hindrances in weight loss measures. 110,111 discussed it is generally assumed that obesity is a risk factor for the development of PCOS and the majority of women with PCOS are either overweight or obese.Importantly, insulin resistance and hyperinsulinemia are drivers for enhanced steroidogenesis in women with PCOS, which provokes hyperandrogenaemia and hyperandrogenic features including hirsutism that are regularly seen in women with PCOS.Conversely, PCOS is associated with increased 5α reductase activity, which catalyzes the conversion of testosterone into 5-dihydroxytestosterone acting as a potent androgen and provoking the breakdown of cortisol.This subsequently enhances hypothalamo-pituitary adrenal axis activity and androgen steroidogenesis. 103Therefore, it is reasonable to conclude that obesity and PCOS are, in part, reciprocally linked.
The complex interaction between increased adiposity and PCOS is depicted in Figure 5.

| The intertwined elements of obesity and type 2 diabetes
The term 'diabesity' describes the simultaneous presence of obesity and type 2 DM and their interconnected relationship, as the risk of type 2 DM increases with higher BMI.The relationship between DM and obesity has been the focus of numerous studies due to the concurrent rise in the prevalence of obesity and type 2 DM worldwide.The pathophysiological mechanisms include adiposity-induced alterations in β-cell and insulin resistance in multiple organs.A significant mechanism linking obesity and DM is the increase in visceral fat caused by the transportation of excess hepatic triglycerides in VLDL to various tissues, including the β-cells of the pancreas, ultimately resulting in β-cell dysfunction and type 2 DM. 112cess body fat, especially intraabdominal fat, is responsible for a multitude of metabolic abnormalities such as increased plasma triglycerides, low HDL cholesterol and beta cell dysfunction.The increase in basal and postprandial plasma insulin levels in obese individuals is caused by increased pancreatic insulin secretion and decreased clearance of portal and peripheral plasma insulin. 85β-cell dysfunction is primarily caused by elevated plasma FFAs and other lipid mediators, such as ceramides and diacylglycerols.

F I G U R E 5
Central events leading to polycystic ovary syndrome (PCOS).Insulin resistance and hyperandrogenism are two synergistic factors that trigger PCOS.The elevated secretion of androgens is caused by intrinsic dysfunction of the ovarian theca cells and dysfunction of the hypothalamus-pituitary gland-ovarian axis.In obese individuals, insulin resistance and hyperinsulinemia alters the pulsation of the pituitary gland, leading to disorderly release of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH).The elevated ratio of LH to FSH in females results in a dysfunctional menstrual cycle, which is a hallmark of PCOS.Additionally, in the early stage of development, there is an increased follicular mass or hypersecretion by follicles, leading to elevated levels of Anti-Müllerian hormone (AMH).AMH can be used as a strong diagnostic predictor for PCOS.Interestingly, obese individuals typically have decreased circulating levels of sex hormone-binding globulin (SHBG) produced by the liver, which is also observed in patients with PCOS.For more details about the pathophysiology of PCOS and factors influencing this endocrine disorder, recent publications provide further information. 149,150ue to nutrition overload and adiposity, adipose tissue, whose function is to maintain energy balance during fasting and feeding, expands and its mass increases due to the accumulation of triglycerides in adipocytes. 114[117][118] Interestingly, individuals with obesity have an impaired ability of insulin to suppress hepatic glucose production. 119Over the years, the activation of inflammatory pathways has been implicated in the pathogenesis of insulin resistance in the obese population.Inflammatory pathways such as IκB kinase (IKKB) and JNK1 are activated by TNF-α, FFAs, diacylglycerols, ceramides, and ROS. 120In obesity, contributors to chronic inflammation include ER stress, decreased adiponectin, increased leptin, macrophage infiltration and lipolysis. 120rthermore, the ectopic accumulation of fat in muscles and adipose tissue in obese individuals causes mitochondrial dysfunction and impaired mitochondrial oxidative activity and ATP synthesis.Obesity also accelerates aging of adipose tissue, increases ROS formation in adipocytes resulting in impaired glucose tolerance and IR.Lastly, impaired translocation of GLUT4 has been implicated in the development of IR in the obese population. 121 summary, a combination of endocrine, neural, and inflammatory factors link obesity to type 2 DM.A holistic approach is necessary to target these defective signaling pathways to effectively manage type 2 DM.

| Obesity -A hallmark feature of cardiovascular disease
Multiple mechanisms have been proposed on how obesity drives structural, functional, and hemodynamic alterations in the development of coronary artery disease, heart failure and arrhythmias.
Obesity has a stronger relationship with ischemic stroke and coronary heart disease.Unhealthy dietary habits and lack of physical activity result in ectopic lipid accumulation and metabolic abnormalities such as dyslipidemia and insulin resistance.These, in turn, increase the risk factors for CVD such as type 2 DM, hypertension, and atherogenesis.In the case of PCOS, the threat of CVD increases due to various triggering factors such as OSA, hypertension, metabolic dysfunction-associated fatty liver disease (MAFLD), and dyslipidemia. 122Visceral fat accumulation promotes adipokine expansion, which, in turn, enhances the recruitment and proliferation of proinflammatory macrophages leading to oxidative stress. 123Collectively, the aforementioned risk factors are direct risk factors for CVD in obesity.
Obesity or being overweight causes an increase in cardiac output and total blood volume, which contributes to both structural and functional changes in the heart.This increase in intravascular volume leads to left ventricular hypertrophy and left ventricular diastolic dysfunction, making individuals more susceptible to heart failure. 124ditionally, the accumulation of fat around the kidneys can compress them, resulting in the upregulation of the RAAS and SNS.This can lead to hypertension and stroke, further worsening heart failure and reducing ejection fraction. 125Another indirect association between obesity and CVD is the impairment of physical activity and the presence of musculoskeletal comorbidities such as osteoarthritis.
These factors can contribute to further weight gain and escalate the risk of developing CVD. 126Various cardiovascular abnormalities are associated with fat mass disorders.These include increased heart rate, left atrial abnormalities, and hemodynamic changes such as increased stroke volume, cardiac output, arterial pressure, and left ventricular stiffness.Structural changes including myocardial fibrosis, left atrial enlargement, left ventricular hypertrophy, right ventricular hypertrophy, and increased pericardial adiposity, are also observed. 124,127Additionally, multiple functional changes have been implicated, such as atherosclerosis, thrombosis, myocardial ischemia, deep vein thrombosis, and pulmonary embolism.
Yet another indirect factor is the increased risk of metabolic syndrome, coronary artery disease, and heart failure in individuals with OSA. 128Furthermore, the RAAS and SNS in individuals with chronic kidney disease can both elevate the risk of CVD in obese individuals.This risk is influenced by inflammation, dyslipidemia, and hypertension, as well as other factors like coronary calcification, coagulation activation, and endothelial dysfunction. 129The primary cause of this strong association is the accumulation of ectopic visceral fat, which promotes chronic inflammation and affects various stages of CVD, including atherosclerosis and thrombosis. 130dothelial dysfunction, linked to CVD, is induced by perivascular adiposity in obese individuals.This adiposity fosters local inflammation and hampers endothelial function. 131The malfunction of adipose tissue results in low-grade inflammation, facilitating immune cell infiltration and leading to insulin resistance, ER stress, and increased ROS production. 132The inflammatory progression of atherosclerosis causes coronary calcification, which is notably more prevalent in individuals with abdominal obesity. 133Pro-inflammatory cytokines boost ROS production and activate redox-sensitive intracellular pathways, increasing the expression of pro-atherogenic genes, such as heightened expression of adhesion molecules like vascular cell adhesion molecule 1 on endothelial cell surfaces, promoting monocyte infiltration into the subendothelial space. 134In summary, the expansion of visceral adipose tissue causes dysregulation of adipokine secretion and increased production of inflammatory cytokines that contribute to insulin resistance, endothelial dysfunction, and a pro-thrombotic state, ultimately increasing the risk of CVD in obese individuals.

| Obesity and cancer
The obesogenic environment is highly complex consisting of alterations in glucose, leptin, adiponectin, glucagon, insulin, cholesterol, and FFAs.Recently, the molecular and cellular processes by which the obese environment affects tumor initiation and progression have been gaining attention.Genetic and non-genetic alterations govern the interactions between obesity and cancer.In obese states, increased triglycerides cause adipose tissue hypertrophy and hyperplasia, contributing to changes in micro and macro environments. 135e satiety-promoting effects of leptin are impaired by cellular leptin resistance in obesity.In addition to decreased energy expenditure, hyperleptinemia has peripheral effects on cancer cells and the tumor microenvironment, particularly helper T cells.For example, leptin acts as a growth-stimulating agent in breast cancer, repressing apoptotic pathways, promoting proliferation, modulating metabolic reprogramming and ROS production.Additionally, leptin is associated with cancer stem cell enrichment and epithelial to mesenchymal transition.Interestingly, leptin controls stem cell phenotype through epigenetic mechanisms controlled by the leptin-STAT3-G9a histone methyltransferase signaling axis. 136sregulation of adiponectin has been implicated in colon, liver, renal and pancreatic cancers.This hormone is an insulin sensitizer in the liver and muscle, balancing glucose and lipid metabolism.Adiponectin stimulates ceramidase activity through AdipoR1 and R2 enhancing pro-apoptotic ceramide catabolism leading to the formation of its downstream anti-apoptotic metabolite sphingosine-1phosphate S1P. 137Strikingly, increased levels of obesity related adipokines such as IL-6, IL-8, and TNF-α are associated with an increased cancer risk.In mouse models, it was reported that a highfat diet induced increased FFAs promote PPARγ signaling which is an upstream regulator of WW domain-containing transcription regulator expression. 138sulin and IGF-1 activate the INSR and the Insulin growth factor-1 receptor (IGF-1R), leading to the stimulation of cell proliferation and protein synthesis pathways for tumorigenesis PI3K/AKT/ mTOR signaling pathway and RAS-MAPK pathways.139 In obese states, adipocytes in expanding adipose tissue, deposit altered amounts of extracellular matrix (ECM) components, causing ECM remodeling and changes in tissue stiffness.These alterations promote the tumorigenic potential of premalignant breast epithelial cells.
Another interesting finding in obese states is the abundant production of collagen VI by the adipocytes. 140This proves that dysregulated single extracellular matrix component can promote tumorigenesis. 141In intestinal cancers, increased FFAs activate PPARγ-dependent signaling to promote tumor initiating capacity.In addition to tumor initiation, increased FFAs and fatty acid binding proteins are associated with increased cancer progression.For example, in ovarian cancer, metastasis of cancer cells is fueled by fatty acids delivered by FABP4 from adipocytes. 142Furthermore, this metastasis is also associated with STAT3/ALDH1 signaling in these cancers.In breast cancer cells, fatty acids activate mTOR and MAPK signaling to facilitate increased glycolytic and aerobic respiration. 143creased FFAs drive the polarization of adipose tissue macrophages towards a metabolically activated phenotype.This, in turn, alters the niche to support breast cancer stemness and tumorigenesis through the IL-6/gp130 signaling axis. 144In summary, the complexity of the obese environment translates into complex molecular drivers of tumors.Further research might unravel potential therapeutic approaches.

| Emerging advances in GLP-1 targeting obesity
GLP-1 agonists have recently gained attention for treating obesity and type 2 diabetes.These drugs are designed to mimic endogenous GLP-1, an incretin hormone produced by L cells in the intestine.GLP-1 levels rise after meals, promoting insulin production and release, reducing glucagon release, slowing gastric emptying, and increasing satiety.Between 2012 and 2014, three extended-release GLP-1 agonists that act centrally were approved for long-term weight management.However, they were quickly cleared by the kidneys due to their short half-life.To improve the pharmacokinetic profile of GLP-1, an approach was developed to create a GLP-1 analogue resistant to degradation by DPP4, an enzyme that breaks down GLP-1 quickly. 145 Liraglutide, structural modifications were made to GLP-1 to extend its half-life to 13 h. 146Similarly, in Semaglutide, Lys26 was attached to a hydrophobic C-18 fatty di-acid moiety to inhibit glomerular filtration.Tirzepatide, developed in 2022 is a dual-acting GLP-RA and GIP-RA, combining the structural features of GLP-1 and exenatide. 147raglutide was the first daily injectable GLP1-RA approved for type 2 diabetes.The next step was the extensive study of Semaglutide in STEP clinical trials.Semaglutide 2.4 mg subcutaneous injections once a week was approved by the FDA for chronic weight management in June 2021. 148Table 1 summarizes the most recent clinical trials on Liraglutide, Semaglutide, and Tirzepatide, and their weight loss outcomes.between obesity and its complications in order to address this complex disease and reduce the global healthcare burden.By unraveling the cellular and molecular signaling network, and gaining a deeper understanding of the cross talk between obesity and the signaling pathways involved in its complications, we can achieve precision medicine in the fight against obesity and its associated comorbidities.

| CONCLUSION
T A B L E 1 Representative clinical studies using GLP-1 agonist to target overweight.

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JOURNAL OF CELL COMMUNICATION AND SIGNALING Obesity increases the risk of several debilitating diseases, such as hypertension, CVDs, MAFLD, type 2 DM, and certain cancers.The population that is overweight or obese is at the highest risk of developing CVD and its associated complications.Additionally, obesity itself is an independent risk factor for CVDs.Obesity can cause complications in the upper and lower gastrointestinal tract due to increased intra-abdominal pressure, including an elevated risk of esophageal cancers.Obesity is the most common risk factor for type 2 DM, which triggers inflammatory pathways, elevated levels of FFAs, adipose tissue hypoxia, and fat accumulation in ectopic locations.Treating obesity is crucial in managing and addressing type 2 DM.The main mechanisms that explain the connection between obesity and high blood pressure involve the activation of the SNS and the RAAS in obese individuals.Excessive fat deposits in the upper respiratory tract of obese individuals can narrow the airway and lead to episodes of hypoxia, resulting in sleep apnea.The majority of women with PCOS are obese, and this condition presents as JOURNAL OF CELL COMMUNICATION AND SIGNALING ovulatory dysfunction, insulin resistance, impaired fertility, hormonal imbalances, and menstrual irregularities.Currently it is discussed, if PCOS and obesity are reciprocally linked.Immediate attention is needed to understand the signaling mechanisms and interactions 155aglutide 1.8 mg/day (n = 232), placebo (n = 115) and open label insulin glargine (n = 234) were used in combination with metformin 1 g twice per day and glimepiride 4 mg/day for a period of 26 weeks.The average weight reduction was 1.8 kg in the liraglutide group compared to 0.42 kg in the placebo group.Liraglutide 1.8 mg per day (n = 233) or exenatide 10 μg twice per day (n = 231) for 26 weeks.The average weight loss was 3.24 kg in the liraglutide group and 2.78 kg in the exenatide group.Tirzepatide was administered at doses of 5, 10 or 15 mg per week to individuals with type 2 diabetes mellitus who were taking insulin glargine, with or without metformin.The study involved 475 participants and lasted for 40 weeks.Body weight reduction by 6.2, 8.2, and 10.0 kg respectively155Surmount 1Tirzepatide was administered at doses of 5, 10 or 15 mg per week in obese individuals without diabetes.The study included a total of 2539 participants over a period of 72 weeks.Weight reduction was observed at 15%, 19.5%, and 20.9% in dosages of 5 mg, 10 mg, and 15 mg, respectively, compared to a 3.1% reduction in the placebo group.