👤 Jean-Philippe Collet

Obesity causes dyslipidemia and is a major risk factor for cardiovascular disease. However, the mechanisms coupling weight gain and lipid metabolism are poorly understood. Brain melanocortin 4 receptors (MC4Rs) regulate body weight and lipid metabolism in mice, but the relevance of these findings to humans is unclear. Here we investigated lipid levels in men and women with obesity due to MC4R deficiency. Among 7,719 people from the Genetics of Obesity Study cohort, we identified 316 probands and 144 adult family members with loss-of-function (LoF) MC4R mutations. Adults with MC4R deficiency had lower levels of total and low-density lipoprotein (LDL)-cholesterol and triglycerides than 336,728 controls from the UK Biobank, after adjusting for adiposity. Carriers of LoF MC4R variants within the UK Biobank had lower lipid levels and a lower risk of cardiovascular disease, after accounting for body weight, compared to noncarriers. After a high-fat meal, the postprandial rise in triglyceride-rich lipoproteins and metabolomic markers of fatty acid oxidation were reduced in people with MC4R deficiency compared to controls, changes that favor triglyceride storage in adipose tissue. We concluded that central MC4Rs regulate lipid metabolism and cardiovascular disease risk in humans, highlighting potential therapeutic approaches for cardiovascular risk reduction. Show less

The prevalence of obesity is increasing worldwide, affecting both children and adults. This obesity epidemic is mostly driven by an increase in energy intake (abundance of highly palatable energy-dense food and drinks) and to a lesser degree a decrease in energy expenditure (sedentary lifestyle). A small proportion of individuals with obesity are affected by genetic forms of obesity, which often relate to mutations in the leptin-melanocortin pathway or are part of syndromes such as the Bardet-Biedl syndrome. These rare forms of obesity have provided valuable insights into the genetic architecture of obesity. Recent advances in understanding the molecular mechanisms that control appetite, hunger, and satiety have led to the development of drugs that can override genetic defects, enabling precision treatment. Leptin deficiency is uniquely treated with recombinant human metreleptin, while those with LEPR, PCSK1, or POMC deficiency can now be treated with the MC4R agonist setmelanotide. This review highlights the most frequent monogenic and syndromic forms of obesity, and the future outlook of precision treatment for these conditions. Show less

The main objective was to carry out a global DNA methylation analysis in a population with gender incongruence before gender-affirming hormone treatment (GAHT), in comparison to a cisgender population. A global CpG (cytosine-phosphate-guanine) methylation analysis was performed on blood from 16 transgender people before GAHT vs. 16 cisgender people using the Illumina© Infinium Human Methylation 850k BeadChip, after bisulfite conversion. Changes in the DNA methylome in cisgender vs. transgender populations were analyzed with the Partek The principal components analysis (PCA) showed that both populations (cis and trans) differ in the degree of global CpG methylation prior to GAHT. The 2-way ANOVA test showed 71,515 CpGs that passed the criterion FDR It is the first time that a global CpG methylation analysis has been carried out in a population with gender incongruence before GAHT. A prospective study before/during GAHT would provide a better understanding of the influence of epigenetics in this process. The main finding of this study is that the cis and trans populations have different global CpG methylation profiles prior to GAHT. Therefore, our results suggest that epigenetics may be involved in the etiology of gender incongruence. Show less

Serum cholesterol efflux capacity, a biomarker that integrates contributors and modulators of the initial step of the reverse cholesterol transport, has been associated with atherosclerosis independently of high-density lipoprotein (HDL) cholesterol level. The authors evaluated the prognostic impact of serum cholesterol efflux capacity on mortality in a large cohort of patients hospitalized for an acute myocardial infarction (MI). Serum cholesterol efflux capacity, cholesteryl ester transfer protein (CETP) activity, total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol, and triglyceride levels were measured in 1,609 consecutive patients admitted with an acute MI. The primary endpoint was all-cause mortality evaluated at 6 years with a median follow-up of 1.9 years (interquartile range: 1.5 to 4.2 years). An analysis by quartile of serum cholesterol efflux capacity was also performed. In a fully adjusted model that included age, sex, traditional cardiovascular risk factors including lipid levels, and prognostic factors of MI, serum cholesterol efflux capacity was a strong predictor of survival (adjusted hazard ratio for mortality per 1-SD increase in serum cholesterol efflux capacity, 0.79; 95% confidence interval: 0.66 to 0.95; p = 0.0132). Patients displaying an elevated serum cholesterol efflux capacity had a marked lower rate of mortality at 6 years (adjusted hazard ratio: 0.54 [0.32 to 0.89]; p = 0.0165) as compared with patients with reduced serum cholesterol efflux capacity. Serum cholesterol efflux capacity, an integrative marker of reverse cholesterol transport pathway and efficacy, was inversely associated with all-cause mortality in MI patients independently of HDL cholesterol level and other risk factors. Show less