Lipid accumulation in non-adipose tissue and lipotoxicity

Abstract

Obesity is a well-known risk factor for the development of type 2 diabetes mellitus and cardiovascular disease. Importantly, obesity is not only associated with lipid accumulation in adipose tissue, but also in non-adipose tissues. The latter is also known as ectopic lipid accumulation and may be a possible link between obesity and its comorbidities such as insulin resistance, type 2 diabetes mellitus and cardiovascular disease. In skeletal muscle and liver, lipid accumulation has been associated with the development of insulin resistance, an early hallmark of developing type 2 diabetes mellitus. More specifically, accumulation of intermediates of lipid metabolism, such as diacylglycerol (DAG) and Acyl-CoA have been shown to interfere with insulin signaling in these tissues. Initially, muscular and hepatic insulin resistance can be overcome by an increased insulin production by the pancreas, resulting in hyperinsulinemia. However, during the progression towards overt type 2 diabetes, pancreatic failure occurs resulting in reduced insulin production. Interestingly, also in the pancreas lipid accumulation has been shown to precede dysfunction. Finally, accumulation of fat in the heart has been associated with cardiac dysfunction and heart failure, which may be an explanation for diabetic cardiomyopathy. Taken together, we conclude that evidence for deleterious effects of lipid accumulation in non-adipose tissue (lipotoxicity) is strong. However, while ample human data is available for skeletal muscle and the liver, future research should focus on lipid accumulation in the pancreas and the heart.

Pathology of Congenital Generalized Lipodystrophy in Agpat2–/– Mice

“…41 The increased insulin resistance in skeletal muscle and liver is initially compensated for by increased insulin production (resulting in hyperinsulinemia), but b-cell depletion and reduced insulin production due to glucolipotoxicity usually occur as disease progresses, eventually resulting in hyperglycemia and overt type 2 diabetes. 52 The precise mechanisms responsible for insulin resistance and pancreatic b-cell failure in diabetes are not yet fully understood, but toxic effects of chronic hyperglycemia and hyperlipidemia (glucotoxicity and lipotoxicity) on b cells are believed to be largely responsible for progression to disease in type 2 diabetes. Because hyperglycemia is a prerequisite for lipotoxicity, the term glucolipotoxicity has been coined to more accurately describe the deleterious effects of glucose and lipids on b-cell function.…”

Oncostatin M is a potential agent for the treatment of obesity and related metabolic disorders: a study in mice

“…However, the mechanisms of obesity-related metabolic diseases are not fully understood. In addition, obesity leads to the ectopic accumulation of lipids in various tissues, including liver, skeletal muscle and heart [4,5]. Especially, accumulation of lipids in hepatocytes induces inflammatory changes in the liver, called non-alcoholic steatohepatitis, which is a risk factor for the development of insulin resistance, liver cirrhosis and hepatocellular carcinoma [6,7].…”

Elevation of pancreatic oxidative stress in STR/Ort mice

“…In the hyperlipidaemic state, steatosis in nonadipose tissues, such as those of the liver, heart, muscle and pancreas, can contribute to an increased risk of hyperinsulinaemia, diabetes, fatty liver and cardiovascular complications (van Herpen and Schrauwen-Hinderling 2008). Recent studies have linked the production of reactive oxygen species (ROS) and oxidative stress to the development of insulin resistance (Ceriello 2000).…”