Cell . . . Discover new "thin" gene: ALK regulates sympathetic nerves to resist weight gain.

Body mass index (BMI) is a complex trait affected by multiple genes and environment.although more than 700 common SNPs related to BMI have been found in large-scale GWAS, only a few genes (such as MC4R, POMC, etc.) have been identified as involved in weight regulation.in addition, most studies in the past have paid more attention to the genetic predisposing factors of BMI increase, but little is known about the reasons why some people resist weight gain.in order to further understand the genetic factors that regulate weight, Josef M. penninger of the Australian Academy of Sciences and Nelle gheldof and Jorg Hager of Nestle ́ Institute in Switzerland published a study entitled "identification of ALK in thinness" online on May 21, 2020.in this study, GWAS analysis was performed in people with low BMI, and it was found that anaplastic lymphoma kinase ALK was associated with wasting phenotype.genetic and mechanism experiments show that ALK is a sympathetic regulator, which controls energy consumption by affecting lipolysis of adipose tissue, and its mutation can resist weight gain.first of all, the case control GWAS analysis was carried out in the Estonian biological bank (egcut): people with BMI of 30-50 percentile as control, those with BMI below 6% as emaciated population, and those with BMI above 95% as obese population (Fig. 1). Two SNPs (rs568057364 and rs202021741) located in ALK gene were found in GWAS, and the two SNPs were located in the same linkage disequilibrium region.in Figure 1, GWAS analysis of the population in the Estonian biobank was performed, followed by a series of follow-up functional experiments.to identify candidate genes causing emaciation, 38 genes were knocked down in Drosophila melanogaster.the results suggested that knockdown of ALK in Drosophila caused a significant decrease in triglyceride levels and abnormal metabolic regulation.in order to further understand the function of ALK gene, the authors constructed ALK knockout mice and analyzed their effects on energy consumption and metabolism in detail.the ALK - / - mice in the standard diet group showed lean, reduced fat content and reduced adipocytes from 5 weeks.however, there was no significant difference in food intake, intestinal digestion and absorption capacity in mice.under high-fat diet, ALK knockout mice still showed obesity resistance and increased energy consumption, suggesting that excessive catabolism may be the reason for their resistance to weight gain.Fig. 2 ALK - / - mouse phenotype: adipocytes in epididymal adipose tissue (epwat) and subcutaneous white adipose tissue (scwat) become smaller. Next, this study is to explore how ALK regulates weight change.considering that ALK is highly expressed in human hypothalamus and paraventricular nucleus of hypothalamus of mice, and participates in the development of nervous system, the author mainly analyzes its role in central nervous system.single cell sequencing showed that ALK + cells were excitatory glutamatergic neurons. the establishment of a paraventricular nucleus specific ALK knockout mouse model also showed resistance to weight gain. furthermore, norepinephrine levels were found in the white adipocytes of ALK deficient mice and lean population samples, indicating that ALK affects adipose tissue through sympathetic nerve in hypothalamus. because norepinephrine promotes lipolysis in adipose tissue, the authors speculate whether ALK affects lipolysis? Indeed, the level of non esterified fatty acids in the adipose tissue of ALK - / - mice was increased; the phosphorylation level of hormone sensitive lipase involved in lipolysis was increased; and the expression of key genes involved in fatty acid oxidation was up-regulated. these data indicate that ALK controls the energy balance of the body by regulating lipolysis and sympathetic nerves in the paraventricular nucleus. in general, the study found a new gene ALK in emaciated individuals. Through detailed genetic and mechanism experiments, it is proved that ALK regulates energy consumption through sympathetic control of adipose tissue lipolysis. understanding the physiological mechanisms of resistance to weight gain may help people to find potential solutions to fight obesity and maintain weight. original link: plate maker: Ke