Expression Of FOXC2 In Adipose And Its Association With Obesity And Insulin Resistance

[Background and objectives]Obesity is a common epidemic disease worldwide, it's also the common risk factor of various metabolic diseases, such as coronary heart disease, hypertension, type 2 diabetes, hyperlipoidemia, etc. The core of its happening lies in the excessive proliferation and differentiation of adipocytes, resulting in redundant adipocytes, nevertheless, there are many other causes. This is the feature of critical importance in the treatment of various kinds of metabolic diseases, therefore, a thorough study in FOXC2 may hold very important position in etiology and therapeutics, it may provide basis for clarifying the mechanism of obesity, insulin resistance and type 2 diabetes, as well as new target goals for their treatment.FOXC2, or to be called MHF1 belongs to human the human winged helix/forkhead transcription factors family. Cederberg and his colleagues screened human adipocyte cDNA library and identified the FOXC2 gene,and thus discovered FOXC2' s function as a key regulator of adipose metabolism. Human FOXC2 gene lies in 16q24.3 of chromosome, it only has one exon, the length of which is 1507 bp, with no intron FOXC2 is expressed in adipose tissues and skeletal muscle of adult mouse and human beings.Through their studies, Cederberg and bis colleagues found that in FOXC2 overexpressing transgenic mouse, transcription factors switching on adipose differention such as C/EBP, PPARγand ADD1/SREBP1 are all upregulated. In Davis KE and his colleagues'study, it has been proved that the expression of FOXC2 blocks the capacity of 3T3-L1 preadipocytes to undergo adipogenesis. This block is characterized by an extensive decrease in the expression of proteins associated with the function of the mature fat cell, most notably C/EBPα, adiponectin, perilipin, and the adiposespecific fatty acid-binding protein, FABP4/aP2.Their study shows that FoxC2 does not affect the ability of PPARγto bind to or transactivate from a PPAR, response element. These data suggest that FoxC2 blocks adipogenesis by inhibiting the capacity of PPARγto promote the expression of a subset of adipogenic genes. Yang and his colleagues found that in human individuals with insulin resistance, the expression of FOCX2 mRNA goes downward, meanwhile, genes relative to the lipogenesis of brown adipose tissues, such as MASK, MAP3K5, pRb, PPARγ,RXRγand PPARγ( PGC-1) all go downward, with a positive correlation relationship. All these illustrate that FOXC2 gene plays a very important role in regulating the differentiation and adipogenesis of adipocytes.The FOXC2 mRNA levels of fat mouse are upregulated by high fat diet. Through studies on Abdominal visceral and subcutaneous adipose tissue of 38 cases of non-diabetes obese subjects, Ridderstrale and his colleagues found that the FOXC2 mRNA inside in abdominal visceral adipose tissue is 12 + 4 times of that in subcutaneous adipose tissue, there is a negative relationship between FOXC2 mRNA of abdominal visceral adipose tissue, total fat quantity and the concentration of fast serum insulin, the FOXC2 mRNA level of abdominal visceral adipose tissue is also relative with that of subcutaneous adipose tissue, whereas there is no notable relationship between the FOXC2 mRNA of subcutaneous adipose tissue and fat quantity, HOMA-IR and limosis insulin. Besides, through 14 cases of hyperinsulinemic-euglycemic clamp test of non-diabetic fat sufferers, and through 40 minutes and 120 minutes of vastus lateralis muscle, it is found that there is a negative relationship between bone muscle FOXC2 mRNA and the concentration of fast insulin, during the period of two hours of clamp, there is no significant upgrading in the level of FOXC2 mRNA in human bone muscle, but bone muscle FOXC2 mRNA can explain independently the difference in the sensitivity of insulin more than 50%. Therefore, the author believed that the upgrading of the expression of FOXC2 in individual human being can play a protection role in resisting the insulin resistance.Yang and his colleagues studied Sweden non-fat non-diabetic male individual with insulin resistance and family history of type-2 diabetes, in comparison with that of matching age, gender, BMI but with no family history of diabetes. subcutaneous adipose tissue was obtained by surgical incision around the umbilicus and percutaneous skeletal muscle tissue from the vastus lateralis muscle. It has been found that in comparison with the individuals those are sensitive to insulin, the expressions of FOXC2 of the individual with insulin resistance are downregulated, meanwhile there is no difference with the expression of FOXC2 of skeletal muscle. Gregorio and his colleagues studied 35 cases of individuals with the BMI span between 22-61kg/m~2, through biopsies of subcutaneous adipose tissue and vastus lateralis muscle, it has been found that the expression level of FOXC2 of human skeletal muscle is 10 times lower than that of the expression level of FOXC2 in subcutaneous adipose tissue. There is a significant negative relationship between the FOXC2 mRNA in subcutaneous adipose tissue and the insulin sensitivity index (SI) , a positive relationship with fast serum insulin, and related with the sensitivity of insulin independent of fat. While in muscle organ, FOXC2 mRNA has no relationship with SI and, nor any relationship with fast serum insulin. To summarize the above, the expression and role of FOXC2 in human adipose tissues is yet to be further studied.[Research design and methods]Study subject: according to obesity diagnosis criteria in Asian Pacific Region from 2000, ?°primary obesity subjects with BMI more than 35kg/ m~2 were chosen. According to the World Health Organization criteria of diagnosis of type 2 diabetes from 1998, obesity subjects without diabetes were chosen.Adipose tissue biopsies: abdominal visceral and subcutaneous adipose tissue biopsies were available from 15 obese non-diabetic subjects undergoing bariatric surgery at Changhai Hospital, Shanghai The tissue biopsies were immediately frozen and kept in liquid nitrogen. Abdominal visceral and subcutaneous adipose tissue biopsies from 8 cases of Chronic cholecystitis sufferers were available for a contrast,Clinical procedures: to test cortisol, ATCH; thyroid hormone; growth hormone ; sex hormone to avoid secondary obesity; OGTT test; fast and post2h plasma glucose; fast and post2h plasma insulin. Expression levels of FOXC2 :protein were measured by Western blot.Data analyses: spass 12.0 software analyses, pair t test, linear correlation analyses. [Results]The expression of FOXC2 of abdominal visceral adipose tissue of the obese group is upgrading comparing with that of the subcutaneous adipose tissue, with a significant difference, P=0.023. Moreover, they are remarkably related. The expression level of FOXC2 of abdominal visceral adipose tissue is remarkably related to the insulin resistance index fast blood sugar/fast insulin, IAI[1/(fast blood sugar~* fast insulin)], e.g, the more the sufferer's sensitivity to the insulin, the higher his FOXC2's level. The expression level of the FOXC2 of abdominal visceral adipose tissue and subcutaneous adipose tissue has no relations with BMI, the WL,HL and WHR.[Disccussion]The potential role of FOXC2 in obesity and insulin resistance was first highlighted in studies in transgenic mice overexpressing FOXC2 in adipose tissue . These mice were leaner and more insulin sensitive and did not become obese with high-fat feeding, suggesting that FOXC2 was a defense against diet-induced obesity. In addition, FOXC2 overexpression led to a pleiotropic effect on gene expression. The subunit composition of PKA was altered, leading to a regulatory subunit that would confer increased PKA sensitivity to cAMP. Such an effect would presumably lead to increased basal lipolysis and, hence, leanness. A subsequent study in humans examined FOXC2 mRNA expression in visceral fat and muscle of obese subjects . The most insulin-resistant subjects in that study demonstrated lower levels of FOXC2 expression in both fat and muscle. Those data tended to confirm the mouse studies and suggested that increased FOXC2 levels may protect against insulin resistance in humans, as it did in the transgenic mice. However, another human study involving only nonobese subjects observed no correlation between FOXC2 and insulin resistance, wherein insulin resistance was measured by the euglycemic clamp. Although this latter study observed no correlation between FOXC2 and glucose disposal rate, insulin-resistant subjects demonstrated lower FOXC2 expression than insulin-sensitive subjects. High calorie diet and low physical activity are important etiological factors for type 2 diabetes.The levmajority of such patients are obese.One major problem in the treatment of type 2 diabetes is to increase insulin sensitivity without promoting adipocyte differentiation (e.g., thiazolidindiones) and/or enlarge triglyceride stores (e.g., insulin) which has the potential of counteracting the initial benefits of such treatments, since more and larger adipocytes will increase insulin resistance. An ideal therapy should not only increase insulin sensitivity but also provide means by which excess energy could be dissipated.The present study indicates that the expression of FOXC2 of abdominal visceral adipose tissue of the obese group is upgrading comparing with that of the subcutaneous adipose tissue, with a significant difference, P=0.023. Moreover, they are remarkably related. The expression level of FOXC2 of abdominal visceral adipose tissue is remarkably related to the insulin resistance index fast blood sugar/fast insulin, IAI[1/(fast blood sugar~* fast insulin)], e.g, the more the sufferer's sensitivity to the insulin, the higher his FOXC2's level. The expression level of the FOXC2 of abdominal visceral adipose tissue and subcutaneous adipose tissue has no relations with BMI, the WL,HL and WHR.The thrifty gene hypothesis put forward already in 1962 states that genetic selection would favor energy conserving genotypes in harsh environments with unstable food supply. At the same time these genes would constitute a risk for developing obesity-related conditions, such as insulin resistance and type 2 diabetes, when food is freely available. FOXC2 could be regarded as an "antithrifry" gene. This is further supported by the findings that FOXC2 transgenic mice demonstrate a relative resistance to diet-induced weight gain as well as dietinduced insulin resistance. The present data raise the question that FOXC2 perhaps serves as an "antithrifry' gene and FOXC2 would be a putative target for treatment aiming at protection from developing insulin resistance and gaining weight when exposed to the affluent environment of current society.[Conclussion]Through investigating the expression of FOXC2 in adipose tissue and its association with obesity and insulin resistance we demonstrate that FOXC2 may play a role in maintaining insulin sensitivity,...