Exploring Therapeutic Targets to Reverse or Prevent the Transition from Metabolically Healthy to Unhealthy Obesity

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.

Short-Term Changes in Metabolically Healthy Overweight/Obesity Status Impact the Susceptibility to Type 2 Diabetes in Chinese Adults

“…Apart from genetic predisposition, poor dietary habits (eg, increase total fat intake), less physical activity, disrupted circadian rhythm, and psychological unhealthy have also considered taking charge of this metabolic shift, which provide us the intervention targets for lifestyle and medical therapy. 32,33 Although we did not confirm the relationship between diet or exercise and the transition probability from MHO to MUO, other studies found that lifestyle interventions significantly improve metabolic conditions without weight loss, partly due to their anti-inflammation function. Polyphenols, which have been found beneficial for cardiovascular risk factors in T2D patients (the TOSCA.IT study), 34 could also extend the lifespan with improved plasma lipid levels and endotoxemia and decreased immune cell infiltration to the adipose tissue in obese mice, which was independent of body weight.…”

EGCG Inhibits Adipose-Derived Mesenchymal Stem Cells Differentiation into Adipocytes and Prevents a STAT3-Mediated Paracrine Oncogenic Control of Triple-Negative Breast Cancer Cell Invasive Phenotype

“…Adipogenesis, as defined by the formation of adipocytes from stem cells [1], and the adipose tissue itself have drawn much attention at the onset of chronic inflammation in metabolic diseases, such as type 2 diabetes mellitus, cardiovascular diseases, and in several types of cancer [2,3]. Among the processes involved in the setting of these diseases, the adipose tissue secretome has been inferred to play a crucial paracrine regulatory role in brain cancer [4], prostate cancer [5], bladder cancer [6], breast cancer [7], and colon cancer [8].…”

Molecular Events Occurring in Lipophagy and Its Regulation in Flaviviridae Infection

“…Recently, increasing investigations into the biological functions of LDs have revealed that LDs are not just inert intracellular storage depots of cellular neutral lipids, but rather a complex and versatile organelle with diverse morphology, which has key roles in lipid metabolism, membrane traffic, protein degradation, and cellular signaling (Henne et al, 2019). The biological function of LDs is to provide ATP to the body by releasing free fatty acids (FFAs) and transporting them to mitochondria for β-oxidation during energy deprivation, fasting, and exercise (Figure 1; Welte and Gould, 2017;Santucci and Canaan, 2018;Dagpo et al, 2020). In mammalian adipocytes, changes in FIGURE 1 | Crosstalk in the metabolic machinery of LDs.…”