Editorial on “Genetics And Metabolic Diseases” Special Issue

Obesity and diabetes are common and complex metabolic diseases, with an increasing prevalence worldwide that results from the interplay of genetic and environmental factors. Recent advances in “-omic” technologies have enabled the discovery of an increasing number of genetic, epigenetic and metabolite markers associated with these conditions. These findings have revealed the complex pathophysiology of these conditions. The challenge now is for researchers and physicians to translate this growing knowledge into action and new clinical approaches. The motivation for this special issue was to provide perspectives and tools to improve risk prediction, prevention, and treatment of metabolic diseases, to better care for patients. In this special issue of Advanced Biology, “Genetics and Metabolic Diseases”, we highlight articles with a translational approach, moving from laboratory discoveries to clinical translation, with an emphasis on metabolic diseases resulting from genetic mutations, such as monogenic obesity and lipodystrophy. Other studies dissect the interrelationship between obesity, diabetes, and lipid metabolism to improve prediction and managed care of complications arising from treatment. In the study by Di Paola et al. (adbi.202200319), the authors address the strict relationship between obesity, diabetes, and dyslipidemia, focusing on the evaluation of how polypeptide N-acetylgalactosaminyltransferase 2 (coded by GALNT2) influence HDL-c and triglycerides levels. While GALNT2 can influence lipid metabolism (e.g., angiopoietin like 3 , apolipoprotein C-IIII and phospolipid transfer protein ) it also affects insulin sensitivity and adipokines. The authors use genetic variants to evaluate the hypothesis that GALNT2 effects on circulating lipoprotein levels go beyond the sole regulation of key lipid metabolism enzyme and also includes effects on insulin sensitivity. In the review by Wang and colleagues (adbi.202300035), a detailed overview is given of the central and peripheral roles of melanocortin 4 receptor (MC4R) in energy metabolism and endocrine hormone homeostasis. Evidence supports the diversity of phenotypes and biased downstream signaling caused by distinct MC4R mutations. This review also includes recent advances in drug development targeting MC4R. MC4R was also evaluated by Zhou et al. (adbi.202300007), reporting six MC4R variants (Y35C, T53I, V103I, R165W, G233S, and C277X) in morbidly obese persons in China. In this morbidly obese cohort, patients with rare MC4R variants seems to benefit the most from metabolic surgery. With the global epidemic of obesity, there is a growing number of patients who need to undergo bariatric/metabolic surgery. In this context, the study by Centeno et al. (adbi.202300001) evaluated the epigenetic changes following bariatric surgery. Specifically, the authors evaluated the DNA methylation remodeling in adipose tissue and identified changes in more than one thousand CpG sites. The GNAS complex locus which is associated with BMI, lipid obesity, and glucose metabolism, harbored the sites with the greatest changes. Remarkably, several of the other sites identified in the study are in genes/loci previously not known to be related to metabolic disorders, stimulating future studies. This study also underscores the role that epigenetic regulation might play in modulating adipose tissue function in obese patients and how these altered functions may potentially be reversed. Excessive fat accumulation also affects the liver and Xue and colleagues (adbi.202200150) described their results inhibiting geranylgeranyl diphosphate synthase (GGPPS) as a novel strategy for treating metabolic associated fatty liver disease (MAFLD). Using a structure-based virtual small molecule screening method, 4-AZ is detected as a GGPPS targeted inhibitor. Further investigation showed that 4-AZ promotes the degradation of GGPPS via the ubiquitin-proteasome pathway and inhibits the accumulation of lipids in primary hepatocytes and decreased lipogenic gene expression through GGPPS. Yu and colleagues (adbi.202200301) identify four unique lamin A/C (LMNA) mutations from six lipodystrophy patients and show how these LMNA variations are characterized by decreased Lamin A/C stability and degradation primarily through the ubiquitin-proteasome system. Ma and colleagues (adbi.202200234) provide a narrative review of the key redox factors, endogenous mechanisms for redox homeostasis, and advanced techniques for dynamic monitoring of redox states. Liu and colleagues (adbi.202300100) discuss the role of diet and gut microbiota interactions on metabolic homeostasis. In addition, they review the alterations of gut microbiota in relation to diet. They emphasize the potential for diet-microbiota crosstalk to influence metabolic homeostasis. One important aspect in the care of patients with metabolic disease is the prevention and treatment of cardiovascular complications. Liu and colleagues (adbi.202200130) demonstrate the therapeutic effects of glucagon-like peptide-1 (GLP-1) on human diabetic cardiomyocytes (DCMs) and establish a novel DCM model for mechanistic based studies. Based on human induced pluripotent stem cells-derived cardiomyocytes, they highlight that both GLP-1 7–36 and GLP-1 9–36 restore cardiomyocyte hypertrophy and abnormal calcium transient frequency. Specifically, that possible targets of GLP-1 7–36 are involved in the regulation of mitotic nuclear division and extracellular matrix-receptor interaction, while targets of GLP-1 9–36 influence kinetochore assembly, complement, and coagulation cascades. Pipino et al. (adbi.202300172) review prediction of cardiovascular disease – a major complication of metabolic disease, – with a focus on how epigenetic and metabolomic markers may predict endothelial dysfunction in type 2 diabetes. Excitingly, the manuscript describes the epigenetic-metabolite relationship and how these can provide novel insights into the physio-pathological processes in early stages of endothelium function. Understanding these processes will enable identification of disease biomarkers and therapies to reduce the cardiovascular burden in metabolic disease. In the review by Geiger et al. (adbi.202300211), details are provided on various epigenetic changes, such as DNA methylation, histone modification, and noncoding RNA, and how they affect immuno-metabolic disease conditions. The authors also describe several environmental factors that influence the epigenetic signature and how these can be transmitted trans-generationally, i.e., influencing the disease traits of the patients and their offspring. The review discusses metabolic traits, such as insulin resistance, systemic inflammation, macrophage polarization, endothelial dysfunction, metabolic cardiomyopathy, and non-alcoholic fatty liver disease. In addition, the review describes currently used drugs (e.g., statins and metformin) as “epigenetic” drugs, suggesting their mechanism of action may be mediated by epigenetic changes. In summary, this special issue includes several studies that aim to advance knowledge and reduce the global burden of metabolic disease. The populations described in these manuscripts are diverse and derived from different countries with different ancestries. Such diversity will further enhance discovery and underscores the value in diverse and equitable approaches in future studies. The care of all patients, recognizing genetic and environmental differences, needs to be considered if we are to be successful in mitigating metabolic diseases worldwide. This editorial was originally intended to be published in volume 7 issue 9, but due to an error in production was not included. To read the complete issue in its intended form please refer to this virtual issue. M.L.M. has received lecture, consultancy, or advisory board fees from Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Novartis, Servier. H.Z. reports no COIs.