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.

Keywords: MAFLD/MASLD; cardiovascular disorders; dyslipidemia; hypertension; obstructive sleep apnea; polycystic ovary syndrome; type 2 diabetes mellitus.

FIGURE 1

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.

FIGURE 2

Pathogenetic events leading to metabolic dysfunction‐associated fatty liver disease (MAFLD) and metabolic dysfunction‐associated 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.

FIGURE 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.

FIGURE 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.

FIGURE 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.,