Influence of menopause on adipose tissue clock gene genotype and its relationship with metabolic syndrome in morbidly obese women

Abstract

Menopausal women exhibit a loss of circadian coordination, a process that runs parallel with a redistribution of adipose tissue. However, the specific genetic mechanisms underlying these alterations have not been studied. Thus, the aim of the present study was to determine whether the development of menopause induces an alteration of the genes that control biological rhythms in human subcutaneous (SAT) and visceral AGE (2012) (VAT) adipose tissue, and whether changes in clock gene expression are involved in the increased risk of developing metabolic syndrome (MetS), which is frequently associated with menopause. To this end, VAT and SAT biopsies were taken in pre-(n=7) and postmenopausal (n=7) women at similar hours in the morning. RNA was extracted, and a microarray analysis was made. Data were confirmed by quantitative real-time polymerase chain reaction. Western blot and immunohistochemical analysis were also performed. When clock gene expression was compared between both groups of women, data in SAT showed that expression of the core clock gene period3 was significantly higher in postmenopausal women, while casein kinase-1δ, E1A-binding protein and cAMPresponsive element were preferentially expressed in the premenopausal group. In VAT, period2 (PER2) and v-myc myelocytomatosis viral oncogene expressions were significantly higher in the postmenopausal group. Western blot analysis indicated that PER2 and PER3 protein expression was also increased in postmenopausal women. In addition, several genes, including PER2, were differentially expressed depending on whether or not the patient met the MetS criteria. We conclude that menopause transition induces several changes in the genotype of the adipose tissue chronobiological machinery related to an increased risk of developing MetS.

Circadian gene variants in cancer

“…It also regulates gluconeogenic genes in response to PGC-1α activation and modulates lipoprotein metabolism by phosphorylating PGC-1β (118, 119). Mutations and/or deregulation of Ck1δ and ε are associated with colorectal, pancreatic, prostate, breast, and ovarian cancers (102, 120–126), neurodegeneration and sleep disorders (127–131), chronic inflammation and aging (132, 133), as well as metabolic syndromes (134, 135). Disruption or deregulation of Ck1δ or ε in mice deregulates circadian homeostasis (136) and increases the risk of mammary carcinogenesis (137) and autoimmune diseases (138).…”

Autophagy in Adipose Tissue

“…An additional interesting possibility arises from the demonstration that expression of autophagy genes exhibits a strong diurnal rhythm and may be regulated by biological clock genes [33,34]. Given the increasingly appreciated role of disrupted biological clocks in metabolic diseases [35,36] and early reports that clock genes may be altered in AT in obesity [37,38], it is tempting to propose disturbed clock gene regulation as a putative cause of, or at least a significant contributor to, altered autophagy in AT. In addition, in many obese individuals AT becomes insulin-resistant.…”

A Period 2 Genetic Variant Interacts with Plasma SFA to Modify Plasma Lipid Concentrations in Adults with Metabolic Syndrome

“…In experimental studies, it was reported that disruption of the core clockwork by mutations in PER2 increases the susceptibility of mice to spontaneous and irradiation-induced tumors (7). PER2 disruption has also been related to different MetS components, such as abdominal obesity (8,9) and glucose metabolism, via influence on the glucose-6-phosphatase gene (10). Indeed, PER2 2/2 mice have a defective feeding rhythm, are hyperphagic and develop obesity when fed a high-fat diet (11), and have altered blood glucose homeostasis (12), demonstrating the striking influence of diet on this gene.…”