Alterations of insulin sensitivity by the implantation of 3T3-L1 cells in nude mice. A role for TNF-α?

Abstract

Visceral fat accumulation is known to be a clinical index for insulin resistance related to obesity [1±3]. Patients with excessive accumulation of visceral fat frequently suffered from metabolic disorders, such as hyperlipidaemia, hypertension and glucose intolerance [4±6]. However, molecular mechanisms for the pathogenesis of obesity-accompanied metabolic disorders are not clear. So far, it has been clarified that adipose cells in visceral areas have different functions both in vivo and in vitro from the cells in subcutaneous areas, and these differences might contribute the pathological significance of visceral fat accumulation for accompanying insulin resistance and hyperinsulinaemia [7]. We have reported that patients with excessive visceral fat accumulation show delayed postprandial triglyceride (TG) metabolism compared to normal subjects, and the disturbed metabolism is, at least in part, caused by reduced lipoprotein lipase (LPL) mass and activity in their sera [8,9]. In accordance with the clinical observations, model rats for Diabetologia (2002) Abstract Aims/hypothesis. Visceral adipocytes have different functions than those from the subcutaneous fat area. These differences could contribute to the pathological significance of excessive visceral fat accumulation for accompanying insulin resistance and hyperinsulinaemia. This study addresses this hypothesis and describes a unique method to clarify whether the functional differences between visceral and subcutaneous adipocytes depend on their anatomical location. Methods. 3T3-L1 cells or TNF-a overexpressing CHO cells were implanted into subcutaneous fat area or mesenteric area as visceral fat area in athymic mice of BALB/C strain. Then, serum insulin, glucose, TNF-a, and several markers of lipid metabolism were measured in the fasting condition. OGTT was also analysed.Results. During the course of glucose loading, the mice which had 3T3-L1 cells implanted into mesenteric area but not into subcutaneous fat area showed remarkably increased serum insulin and TMF-a concentrations, compared to the control mice. Moreover, serum insulin concentrations of the mice, implanted with TNF-a overexpressing cells into subcutaneous fat area, were apparently higher than that of control mice. Conclusion/interpretation. This method of implanting adipose cells into subcutaneous or visceral fat area showed high TNF-a concentration and insulin resistance by the adipose cells in visceral area of nude mice. Furthermore, we found that the functional significance of visceral fat accumulation for TNF-a-induced insulin resistance is partly caused by the interaction of adipocytes with surrounding conditions in mesenteric area. [Diabetologia (2002) 45:518±526]

Improved glucose tolerance in mice receiving intraperitoneal transplantation of normal fat tissue

“…The first notion is supported by findings that intra-abdominal fat mass reduction improves insulin sensitivity in rats [4], whereas implantation of cultured adipocytes into the peritoneal cavity of mice induces insulin resistance [11].…”

Impaired glucose tolerance is accompanied by decreased insulin sensitivity in tissues of mice implanted with cells that overexpress resistin

“…Eight-week-old ICR nude mice were injected subcutaneously with either 1×10 7 cells transfected with resistin cDNA (R-mice) or with 1×10 7 mock cells (M-mice). The injection through 21G needles into subcutaneous areas of nude mice was performed under anaesthetisation, as described [6,7]. Mice were housed in micro-isolator cages under specific pathogenfree conditions throughout the experiments.…”

“…We have recently established a cell implantation method using established cultured pre-adipocytes or cells transfected with complementary DNA (cDNA) for the analysis, in mature mice, of glucose and lipid metabolism, both of which are closely related to visceral fat accumulation [6,7]. The cells implanted into visceral, and not subcutaneous, areas express TNF-α mRNA, and the bioactive peptide secreted causes decreased insulin sensitivity in muscle [6].…”

“…The cells implanted into visceral, and not subcutaneous, areas express TNF-α mRNA, and the bioactive peptide secreted causes decreased insulin sensitivity in muscle [6]. Furthermore, TNF-α-induced insulin resistance in muscle is reversed by treatment with thiazolidinedione (TZD) [7].…”

Diabetologia 1998?2003

“…The final selection is jointly made by the Editor-inChief and the Deputy Editors based on the paper's evaluation by its respective referees and on the suggestions given by the Editorial Board members. At this year's Diabetes-Congress in Paris it was a great pleasure to give the first Annual Best Paper Awards to Dr. M. Trento [3] from Italy (clinical science) and to Dr. M. Shibasaki [4] from Japan (basic science).…”