Editorial: Strategies to overcome metabolic syndrome and related diseases

It has been reported that up to 87% of individuals with MetS have dyslipidemia (3). Given this, research into the key factors regulating lipid homeostasis in MetS and its comorbidities has received a vast amount of attention. In this Research Topic, Nauli et al. explored the effects of sex hormones on the size of intestinal lipoproteins that carry dietary lipids to the periphery (4). Compared to women, men are more prone to central obesity, one of the five conditions that comprise MetS. Using the conscious lymph fistula mouse model, the authors discovered that male mice produced larger intestinal lipoproteins than female mice when intraduodenally infused with lipid emulsion (4). Larger lipoproteins may contribute to central obesity by facilitating increased fat uptake in visceral abdominal adipose tissue. Further investigations leveraging the Caco-2 cell model showed that testosterone significantly increased the size of lipoproteins in a dose-dependent manner (4). Regarding whole-body cholesterol balance, Banerjee et al. reported that, unlike the Aster-B protein, which plays an essential role in cholesterol transport and downstream esterification, the non-vasicular Aster-C protein (encoded by Gramd1c gene) played a minor role in whole-body cholesterol balance in a sophisticated study including divergent dietary cholesterol and Gramd1c knockout mouse model (5). The gut hormone glucagon-like peptide-2 (GLP-2) has been shown to play pleiotropic roles in regulating lipid handling in the intestine, which is important for maintaining energy homeostasis and cardiometabolic health. In the review by Mukherjee and Xiao, the authors elucidated the mechanisms of GLP-2 in regulating post-prandial lipid absorption and post-absorptive release of intestinally stored lipids (6). While further summarizing the role of GLP-2 in metabolic disorders, the authors discussed the opportunities to promote health benefits beyond its current clinical use for treating shortbowel syndrome by manipulating GLP-2 mediated pathways (6).MetS is closely linked to dysregulated energy homeostasis. Engaging in daily physical activities has become the first choice in clinics for managing MetS. Physical activities are well known for body weight management by promoting energy expenditure. However, the impact of physical activities on CVD-related HDL function has yet to be further studied. In a human study including healthy lean, obese, and type 2 diabetic subjects, Zhu et al. demonstrated that a short-term highintensity interval training (HIIT) program improved HDL function depending on metabolic contexts, correlating with improvements in blood lipid profile (7). This study showed that triacylglycerol content in HDL particles may negatively affect the anti-atherogenic function of HDL (7). Furthermore, Sadler et al. quantified the impact of protonophore treatment on wholebody energetics in mice housed at 30 o C, a thermoneutral housing that may mask the effects of anti-obesity strategies on energy expenditure (8). They observed that mice housed at 30 o C showed reduced basal energy expenditure compared to 24 o C controls, and protonophore treatment markedly increased energy expenditure, resulting in reduced adiposity in mice housed at 30 o C (8). Nicotinamide N-methyltransferase (NNMT) is involved in energy expenditure by lowering NAD + content via catalyzing the methylation of nicotinamide. Sun et al. reviewed the current understanding of the role of NNMT in MetS (9). Single nucleotide variants in the NNMT gene are significantly correlated with disturbances in energy metabolism; elevated NNMT gene expression is notably observed in the liver and white adipose tissues of obese individuals (9). In animal models, knockdown NNMT expression with RNAi strategies or small molecule inhibitors improved MetS-related diseases (9).Lipodystrophy syndromes are rare diseases, and delays in diagnosis may predispose to the development of severe metabolic complications and end-organ damage. A rapid action plan was developed by Fourman et al. using insights gathered through a series of advisory meetings with clinical experts from multiple countries (10). The Rapid Action Plan includes clinical and family history, physical exams and laboratory criteria, diagnostic tools of imaging and genetic testing, as well as guidelines for the syndrome treatment and management (10). Along with a commentary article by Massey and Zhu, discussions in the Rapid Action Plan highlighted the significant role of adipose tissues in MetS (10; 11). Another clinically relevant research article in this Research Topic is by Bukara-Radujkovic et al., who demonstrated the role of glycemia risk index in managing blood glucose in routine clinical practice by exploring the correlation of traditional parameters, such as HbA1c, and novel parameters, including glycemia risk index and time-inrange, in pediatric patients with type 1 diabetes (12).Additionally, Li et al. highlighted the significant role of astrocytes in bridging MetS and cognitive dysfunction (13). Systemic inflammation and endocrine disruption in MetS may drive neurodegeneration mediated by astrocytes, which sense and integrate metabolic signals with neurological function (13). In this review, Li and co-authors summarized the alterations in astrocyte phenotypic characteristics in MetS, which could possibly serve as a diagnostic marker or even a therapeutic target for MetS-associated cognitive dysfunction (13). Furthermore, El-Deen et al. explored the impact of co-administration of apricot kernels and caffeine on MetS in an animal model of diabetes, and Yi et al. showed that acetaminophen administration may improve outcomes in critically ill patients with gout and hypertension (14). By analyzing data from the NHANES 2013-2018 survey cycle, Chen et al. observed a negative association between chloroform and type 2 diabetes in older adults in the United States (15).Moreover, Shi reviewed a potential therapeutic target, while Lu et al. reviewed a novel strategy for MetS and related diseases in this Research Topic. Salt-inducible kinases (SIKs) are serine/threonine kinases of the adenosine monophosphate-activated protein kinase family (16). Shi summarized the diverse roles of SIKs in sodium sensing and salt intake, vascular remodeling, pulmonary arterial hypertension, cardiac hypertrophy and ischemia, inflammation, fibrosis, and MetS (16). Interestingly, SIKs are broadly expressed in relevant metabolic tissues, such as adipose tissues and the liver, and play essential roles in mediating insulin action, lipid metabolism, and energy expenditure (16). Pharmaceutical inhibition of SIK activity has shown therapeutic potential in various disease models, including inflammatory and fibrotic diseases (16). Genetic variants in SIK genes have also been shown to be linked with alterations in blood lipid panels, however, the potential clinical relevance of SIK for dyslipidemia is yet to be studied further (16). Regarding the natural supplements for treating MetS and related diseases, Lu et al. reviewed the role of naringin in treating atherosclerosis (17). Naringin is a flavonoid abundantly found in grapefruit and tomatoes. In the liver, naringin can be converted into naringenin by naringinase, which process may be involved in glycemic control (17). Lu et al. summarized the anti-atherogenic effects of naringin in lowering blood pressure, improving dyslipidemia, protecting endothelium, and inhibiting vascular smooth muscle cell proliferation and migration (17). However, the underlying mechanism is not yet conclusive.The editor team of this Research Topic would like to thank all the authors, reviewers, and readers who have contributed to this collection. With all your support, we hope this collection may add a piece of the puzzle to the whole picture of MetS while providing a beam of light for future studies in this research field.

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