Genetic Effects of FTO and MC4R Polymorphisms on Body Mass in Constitutional Types

Sasang constitutional medicine (SCM), a Korean tailored medicine, categorizes human beings into four types through states of physiological imbalances and responsiveness to herbal medicine. One SCM type susceptible to obesity seems sensitive to energy intake due to an imbalance toward preserving energy. Common variants of fat mass and obesity associated (FTO) and melanocortin 4 receptor (MC4R) genes have been associated with increased body mass index (BMI) by affecting energy intake. Here, we statistically examined the association of FTO and MC4R polymorphisms with BMI in two populations with 1370 Koreans before and after SCM typing, and with the lowering of BMI in 538 individuals who underwent a 1-month lifestyle intervention. The increased BMI replicated the association with FTO haplotypes (effect size ≃ 1.1 kg/m2) and MC4R variants (effect size ≃ 0.64 kg/m2). After the lifestyle intervention, the carriers of the haplotype represented by the minor allele of rs1075440 had a tendency to lose more waist-to-hip ratio (0.76%) than non-carriers. The constitutional discrepancy for the accumulation of body mass by the effects of FTO and/or MC4R variants seemed to reflect the physique differences shown in each group of SCM constitutional types. In conclusion, FTO and MC4R polymorphisms appear to play an important role in weight gain, while only FTO variants play a role in weight loss after lifestyle intervention. Different trends were observed among individuals of SCM types, especially for weight gain. Therefore, classification of individuals based on physiological imbalance would offer a good genetic stratification system in assessing the effects of obesity genes

Nuclear rupture at sites of high curvature compromises retention of DNA repair factors.

The nucleus is physically linked to the cytoskeleton, adhesions, and extracellular matrix-all of which sustain forces, but their relationships to DNA damage are obscure. We show that nuclear rupture with cytoplasmic mislocalization of multiple DNA repair factors correlates with high nuclear curvature imposed by an external probe or by cell attachment to either aligned collagen fibers or stiff matrix. Mislocalization is greatly enhanced by lamin A depletion, requires hours for nuclear reentry, and correlates with an increase in pan-nucleoplasmic foci of the DNA damage marker γH2AX. Excess DNA damage is rescued in ruptured nuclei by cooverexpression of multiple DNA repair factors as well as by soft matrix or inhibition of actomyosin tension. Increased contractility has the opposite effect, and stiff tumors with low lamin A indeed exhibit increased nuclear curvature, more frequent nuclear rupture, and excess DNA damage. Additional stresses likely play a role, but the data suggest high curvature promotes nuclear rupture, which compromises retention of DNA repair factors and favors sustained damage

Matrix elasticity regulates lamin-A,C phosphorylation and turnover with feedback to actomyosin

SummaryTissue microenvironments are characterized not only in terms of chemical composition but also by collective properties such as stiffness, which influences the contractility of a cell, its adherent morphology, and even differentiation [1–8]. The nucleoskeletal protein lamin-A,C increases with matrix stiffness, confers nuclear mechanical properties, and influences differentiation of mesenchymal stem cells (MSCs), whereas B-type lamins remain relatively constant [9]. Here we show in single-cell analyses that matrix stiffness couples to myosin-II activity to promote lamin-A,C dephosphorylation at Ser22, which regulates turnover, lamina physical properties, and actomyosin expression. Lamin-A,C phosphorylation is low in interphase versus dividing cells, and its levels rise with states of nuclear rounding in which myosin-II generates little to no tension. Phosphorylated lamin-A,C localizes to nucleoplasm, and phosphorylation is enriched on lamin-A,C fragments and is suppressed by a cyclin-dependent kinase (CDK) inhibitor. Lamin-A,C knockdown in primary MSCs suppresses transcripts predominantly among actomyosin genes, especially in the serum response factor (SRF) pathway. Levels of myosin-IIA thus parallel levels of lamin-A,C, with phosphosite mutants revealing a key role for phosphoregulation. In modeling the system as a parsimonious gene circuit, we show that tension-dependent stabilization of lamin-A,C and myosin-IIA can suitably couple nuclear and cell morphology downstream of matrix mechanics