• To determine the effects of GIP on HSL gene expression, protein expression and HSL activity and the changes in LPL activity within human adipose tissue induced by GIP [ Time Frame: At baseline and after 4 hours of continuous infusion ] [ Designated as safety issue: No ]
  

• To determine the role of GIP in adipocytokine gene expression and secretion from human subcutaneous adipose tissue [ Time Frame: Baseline and after 4 hours of continuous infusion ] [ Designated as safety issue: No ]
  

Other: GIP (glucose dependent insulinotropic peptide) infusion
an intravenous infusion of GIP (glucose dependent insulinotropic peptide)or placebo will be administered at a rate of 2 pmol/kg/min and maintained for 240 minutes.

GIP (glucose-dependent insulinotropic polypeptide) is one of the two main incretin hormones secreted by the enteroendocrine K-cells of the gastrointestinal tract in response to ingestion of carbohydrate and lipid-rich meals. Data emerging from studies in animal models and cultured human adipocytes support a physiological role for GIP in the adipocyte response to chronic exposure to nutritional excess. The mRNA encoding the GIP receptor has been detected in human subcutaneous and omental white adipose tissue as well as in human adipocyte culture systems. Adipose tissue stores excess energy in the form of triacylglycerols (TGs) and mobilizes these stores in the form of free fatty acids (FFAs) in order to meet the energy demands of the organism, a process known as lipolysis. Lipoprotein lipase (LPL) is the enzyme responsible for the hydrolysis of lipoprotein-TG in order to deliver fatty acids to peripheral tissues including the adipose tissue. GIP is known to exert a stimulatory effect on LPL. Mobilization of fat stored in adipose tissue is mediated by hormone-sensitive lipase (HSL) via hydrolysis of TGs. An imbalance between TG synthesis and hydrolysis by favouring fatty acid uptake and esterification may affect energy homeostasis leading to fat accretion within the adipose tissue and contributing to the pathogenesis of obesity.

We hypothesize that GIP exerts its effects by downregulating HSL gene expression, protein expression and HSL activity and by increasing LPL activity within human adipose tissue. Moreover, we propose that GIP is also a regulator of adipokine secretion from human subcutaneous tissue. The proposed study will shed more light on the interactions between gut hormones and adipose tissue. If our original hypothesis is confirmed i.e. that GIP plays a role in the dynamic regulation of human adipose tissue, then inhibition of this hormone will emerge as a promising potential anti-obesity target.

For this pilot study two groups will be studied: six lean (BMI 20-25 kg/m2) male subjects with normal glucose tolerance and 6 male obese (BMI >30 kg/m2) subjects also with normal glucose tolerance. All subjects will be infused for 4 hours with GIP at a rate of 2pmol/kg/min and with placebo on a second occasion. Adipose tissue needle biopsies will be obtained from all subjects during both visits, once in the basal state (before the initiation of the peptide/placebo infusion) and then repeated at the end of the period of infusion. These procedures will be followed by gene expression profiling of the specific genes of interest such as HSL and adipokines.