The role of osteopontin in adipose tissue inflammation

Obesity has recently been found to be associated with adipose tissue infiltration with macrophages (MPh) mediating a chronic low-grade inflammation that appears to cause development of insulin resistance and type 2 diabetes mellitus. So far little is known about molecular mechanisms underlying obesity-associated adipose tissue MPh infiltration and the distinct activated type of adipose tissue MPhs (ATMs) as found in obesity. Osteopontin (OPN) is a pro-inflammatory cytokine and crucially involved in MPh migration and pathogenesis of various inflammatory disorders but a link to obesity-induced insulin resistance has not been elucidated yet. According to previous data particularly from our own laboratory, OPN gene expression in adipose tissue is highly upregulated in obesity particularly when mice are fed a high-fat diet rich in saturated fatty acids. Polyunsaturated fatty acids (PUFA) of the n-3 family efficiently reversed high-fat diet-induced MPh infiltration and OPN expression. We hypothesize that OPN expression is crucially involved in the development of obesity-induced adipose tissue inflammation. It is the aim of the proposed project to investigate a possible role of OPN in (A) ATM activation and function and (B) obesity- and high-fat diet-induced adipose tissue infiltration with MPh including its metabolic consequences. Since n-3 PUFA are the only means known to downregulate OPN expression in adipose tissue to date, mechanisms and consequences of PUFA-induced alterations in OPN expression are to be evaluated as well. Hence, by elucidating the pathophysiological relevance of this specific molecular mechanism for the induction of obesity-induced adipose tissue inflammation and its suppression by n-3 PUFAs this project could significantly contribute to our understanding of the pathophysiology of adipose tissue inflammation and its prevention. This information could provide a basis for the identification of novel strategies and drug targets for the prevention and treatment of type 2 diabetes including recommendations on functional food quality.

Obesity leads to diabetes and cardiovascular disease (heart attack, stroke) and its epidemic-like spread makes it a no. 1 problem for health care in industrialized countries. Inflammatory alterations associated with obesity are an important link to insulin resistance (i.e. reduced action of insulin) that underlies development of diabetes and cardiovascular disease. Data from this project have demonstrated that a particular inflammatory molecule, called osteopontin, critically contributes to the development of inflammation and insulin resistance in obesity. The chronic low-grade inflammation associated with obesity primarily originates from fat (adipose) tissue. We have searched for molecules that critically promote fat inflammation in order to identify potential novel targets to prevent diabetes and cardiovascular disease in obese patients. Osteopontin is an inflammatory protein that we found dramatically upregulated in fat tissue and also in livers from obese compared to lean individuals and mice. These data warranted functional studies on the role of osteopontin in obesity. Studies with mice that were genetically deficient of osteopontin exhibited a much better sensitivity to the action of insulin compared to mice expressing this protein. Thus osteopontin critically contributes to insulin resistance in obesity. Sophisticated metabolic analyses of the insulin resistance in obese mice in presence of absence of osteopontin revealed that insulin action was abolished specifically in liver. Genetically osteopontin deficient mice lack this protein already during development of obesity whereas treatment of obesity and its complications will start only later in life after obesity has established. In order to understand whether the detrimental effects of osteopontin on insulin sensitivity in obesity were reversible, we neutralized osteopontin action by use of specific antibodies in obese mice. By this means we could significantly improve insulin action and reverse inflammatory alterations in obesity. Hence this project provided the basis for a novel strategy to prevent diabetes and cardiovascular disease in obesity by interfering with osteopontin action. Further studies on the action of osteopontin revealed that osteopontin elicits an inflammatory response in macrophages, i.e. inflammatory cells that infiltrate obese fat tissue, providing evidence for a direct action in these cells. Moreover, osteopontin also hampered the development of and insulin action in fat cells thereby interfering with the function of fat tissue. All together this project identified osteopontin and proved the concept of osteopontin as a novel target molecule for the prevention of diabetes, heart attack and stroke in obese patients. Further studies are required to identify the molecular mechanisms of osteopontin action in obesity in order to develop small molecule drugs.