Insulin inhibits leptin receptor signalling in HEK293 cells at the level of janus kinase-2: a potential mechanism for hyperinsulinaemia-associated leptin resistance

Abstract

The role of leptin in the pathogenesis of obesity has been intensively studied in recent years [1]. Many studies in obese patients found an apparent discrepancy between circulating leptin levels and leptin effects, suggesting that leptin resistance might be a common phenomenon in obese individuals [1]. The mechanisms causing leptin resistance are not, however, clear. Structural defects of the leptin receptor, associated with a loss of function which might cause cellular leptin resistance, do not seem to be a common cause in human beings [2] indicating that abnormalities in postreceptor signalling elements, either genetically determined or caused by regulatory mecha- Diabetologia (2001) Abstract Aims/hypothesis. Leptin resistance in obese humans seems to be predominantly caused by signalling abnormalities at the post receptor level. Leptin resistance in obese individuals is frequently associated with insulin resistance and pronounced hyperinsulinaemia indicating a negative crosstalk of the insulin and leptin signalling chain.Methods. This hypothesis was tested using a cell model of peripheral leptin signalling, i. e. insulin-secreting cell lines (RINr1046±38). Mechanisms for a crosstalk between the insulin and leptin signalling pathway were also studied in rat-1 and HEK293 cells overexpressing elements of the insulin and leptin signalling chain.Results. The effects of leptin on insulin secretion are completely cancelled by a 4-h preincubation with 1 nmol/l insulin, supporting the hypothesis of a negative crosstalk of insulin and leptin signalling. We investigated the potential molecular mechanisms in more detail in HEK293 cells and Rat-1 fibroblasts that overexpressed proteins of the insulin and leptin signalling chain. Leptin (60 ng/ml) stimulated autophosphorylation of JAK-2 in HEK 293 cells. This leptin effect could be inhibited by simultaneous treatment of cells with insulin. Furthermore, overexpression of the insulin receptor in HEK 293 cells clearly reduced JAK-2 phosphorylation and led further downstream to a diminished phosphatidylinositol 3-kinase activity. The inhibitory effect of the insulin signal could be partially prevented by transfection of the cells with an inactive mutant of the tyrosine phosphatase SHP-1. Conclusion/interpretation. In summary, our data suggest that the insulin receptor signalling pathway interferes with leptin signalling at the level of JAK-2. Inhibition of JAK-2 phosphorylation might occur through SHP-1-dependent pathways, indicating that hyperinsulinaemia contributes to the pathogenesis of leptin resistance. [Diabetologia (2001

Plasma Leptin Concentration in Tamoxifen-Treated Ovariectomized Rats

“…Further, we show that the plasma insulin level is higher in the tamoxifen group than in the control group without significant differences in the plasma glucose levels between the two groups. In recent interesting papers, hyperinsulinemia was shown to contribute to the pathogenesis of leptin resistance [35] and tamoxifen induced hypertriglyceridemia associated with diabetes [36]. Therefore, our present data indicate that tamoxifen might induce insulin resistance associated with a lowering of plasma leptin levels.…”

The role of oestrogen in the pathogenesis of obesity, type 2 diabetes, breast cancer and prostate disease

“…In effect, this builds the total fat mass to further increase leptin (Castracane et al, 1998) and adipocyte oestrogen output (Vona Davis et al, 2007), which initiates the process of impaired leptin receptor signalling (Kellerer et al, 2001;Strat et al, 2005;Garofolo et al, 2006;Ishida-Takahashi et al, 2006).…”

Regulation of adipocytokines and insulin resistance

“…Leptin inhibits appetite and weight gain by decreasing orexigenic and increasing anorexigenic peptide expression in the hypo-thalamus [109]. Studies concerning direct effects of leptin on insulin sensitivity in insulin-responsive tissues such as liver, muscle, and fat have yielded contradictory results; however, there is general agreement that leptin expression and secretion are increased in obesity and that a strong correlation exists between body fat stores and leptin plasma concentrations (Table 1) [109,110,111]. Consistent with its appetitesuppressive effect, leptin expression is stimulated upon feeding and suppressed during starvation [112].…”