Adverse drug effects on glucose and lipid metabolism: is human adipose tissue of importance?

Abstract: Many pharmacological agents that are widely prescribed in clinical practice have adverse metabolic effects, such as hyperglycaemia, insulin resistance, and diabetes. Among such drugs are antipsychotics, prescribed for treatment of schizophrenia; statins, which inhibit cholesterol synthesis and prevent cardiovascular events; finally, potent anti-inflammatory agents, glucocorticoids. This thesis is focused on investigating the direct effects of second-generation antipsychotics (SGAs), statins, and glucocorticoids on human adipose tissue metabolism and inflammation, particularly in the light of macrophage-adipocyte cross talk.In Paper I, the direct effects of SGAs on adipose tissue glucose and lipid metabolism were studied. SGAs had a mild effect on adipocyte glucose uptake and lipolysis at therapeutic concentrations. At supra-therapeutic concentrations, the drugs demonstrated anti-inflammatory potential, reducing the expression of pro-inflammatory genes in the adipose tissue.In Paper II, the anti-inflammatory potential of SGAs and dexamethasone was further explored. The effects of the drugs on macrophage phenotype and communication with adipocytes were addressed. SGAs at supra-therapeutic concentrations exerted mild anti-inflammatory effects on macrophages, while dexamethasone acted as a potent anti-inflammatory agent and promoted alternatively activated M2 macrophage phenotype. Macrophages, in turn, induced marked upregulation of pro-inflammatory genes in adipocytes, which was partially reversed by dexamethasone, while SGAs had no effects on macrophage-adipocyte communication.In Paper III, we examined the association of statin therapy on systemic insulin resistance and direct effects statins on human adipose tissue and pancreatic islets functions. We also studied association of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the enzyme involved in cholesterol synthesis, and genetic inhibition of HMGCR seen with certain polymorphisms with adipose tissue and plasma metabolome. Our study demonstrated minor direct effects of statins on human adipose tissue metabolism and insulin secretion in pancreatic islets. We observed that HMGCR expression was associated with a number of metabolic and mitochondrial pathways in the adipose tissue, while LDL-lowering HMGCR polymorphism was negatively associated with plasma phosphatidylcholines and sphingomyelins. In Paper IV we studied the effects of glucocorticoids on adipose tissue fibrosis, particularly in terms of macrophage-preadipocyte communication. Together with inflammation, adipose tissue fibrosis impairs adipocyte metabolism and functions. We observed that glucocorticoids at high concentrations have pro-fibrotic effects in adipose tissue. Macrophage-preadipocyte co-culture data showed that macrophages stimulate phenotypic switch of preadipocytes to pro-fibrotic myofibroblasts, and this effect was exacerbated by dexamethasone. Our findings suggest that pro-fibrotic effects of excess glucocorticoids on adipose tissue are at least partially mediated via their effects on macrophage-preadipocyte communication.We conclude that SGAs and statins have a mild direct effect on adipose tissue metabolism and their diabetogenic effects could to be induced via other organs, such as brain, liver or muscle. By contrast, glucocorticoids, directly impair adipose tissue metabolism and exacerbates adipose tissue fibrosis, which could be one of the contributing factors to their metabolic adverse effects.