Abstract
The prevalence of obesity and obesity-related metabolic comorbidities are rapidly increasing worldwide, placing a huge economic burden on health systems. Excessive nutrient supply combined with reduced physical exercise results in positive energy balance that promotes adipose tissue expansion. However, the metabolic response and pattern of fat accumulation is variable, depending on the individual’s genetic and acquired susceptibility factors. Some develop metabolically healthy obesity (MHO) and are resistant to obesity-associated metabolic diseases for some time, whereas others readily develop metabolically unhealthy obesity (MUO). An unhealthy response to excess fat accumulation could be due to susceptibility intrinsic factors (e.g., increased likelihood of dedifferentiation and/or inflammation), or by pathogenic drivers extrinsic to the adipose tissue (e.g., hyperinsulinemia), or a combination of both. This review outlines the major transcriptional factors and genes associated with adipogenesis and regulation of adipose tissue homeostasis and describes which of these are disrupted in MUO compared to MHO individuals. It also examines the potential role of pathogenic insulin hypersecretion as an extrinsic factor capable of driving the changes in adipose tissue which cause transition from MHO to MUO. On this basis, therapeutic approaches currently available and emerging to prevent and reverse the transition from MHO to MUO transition are reviewed.
Highlights
These include cardiometabolic disorders such as non-alcoholic steatohepatitis (NASH), type 2 diabetes (T2D), polycystic ovary syndrome (PCOS) and atherosclerotic cardiovascular disease (ASCVD), as well as disorders not usually classified as cardiometabolic, such as chronic kidney disease, mental health conditions and various types of cancer [11,12,13,14]
In vitro studies have shown that upon hormonal stimulation, committed preadipocytes undergo differentiation triggered by the expression of early CCAAT/enhancer binding protein (C/EBP) β and δ and late transcriptional factors peroxisome proliferator activated receptor-γ (PPAR-γ) and C/EBP-α [36]
While multiple tissues including gut, liver, skeletal muscle and kidney are clearly involved in amino acid metabolism, transcriptome analysis of adipose tissue obtained from these groups showed impaired expression of several genes associated with Branched-chain amino acids (BCAA) catabolism [154]
Summary
Obesity is a complex condition that occurs due to abnormal or excessive fat accumulation in the body and is diagnosed at a body mass index (BMI) of ≥ 30 kg/m2 [1]. With increasing prevalence of overweight and obesity in women of childbearing age, pregnant women are more likely to be overweight or obese and have hyperglycemic disorders such as gestational diabetes and type 2 diabetes (T2D) [7,8,9] Their offspring are more likely to be born large for gestational age due to fetal hyperinsulinemia and excess adipose tissue accumulation and be at higher risk of childhood obesity, metabolic syndrome (MetS) and T2D [7,8]. Obesity is associated with increased risks for a plethora of comorbidities These include cardiometabolic disorders such as non-alcoholic steatohepatitis (NASH), T2D, polycystic ovary syndrome (PCOS) and atherosclerotic cardiovascular disease (ASCVD), as well as disorders not usually classified as cardiometabolic, such as chronic kidney disease, mental health conditions and various types of cancer [11,12,13,14]. Development of effective interventions to reduce the incidence of obesity and its related comorbidities are urgently needed, with particular focus on preventing the amplification of this health crisis across generations [10]
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