Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation

Abstract

Obesity and type 2 diabetes mellitus are the major noncommunicable public health problem of the 21st century. The best strategy to tackle this problem is to develop strategies to prevent/treat obesity. However, it is becoming clear that despite successful research identifying weight regulatory pathways, the development of the obesity epidemic is outpacing scientific progress. The lack of success controlling the obesity epidemic in an aging population will result in another subsequent uncontrolled epidemic of complications. Our research focuses on the mechanisms causing lipotoxicity aiming to identify suitable strategies to prevent or at least retard the development of the metabolic syndrome. Previous work using transgenic and knockout mouse models has shown an interplay between white adipose tissue and skeletal muscle linking fatty acid (FA) synthesis with reciprocal effects on FA oxidation. Work from our lab and others suggests that defective adipose tissue is a key link between obesity, insulin resistance and type 2 diabetes mellitus by promoting the development of lipotoxicity in peripheral tissues. We propose a series of models to describe the process by which the adipose tissue could react to an energy-rich environment and responds depending on genetic and physiological factors, impacting on the functions of other peripheral tissues. We suggest that by examining hypotheses that encompass multiple organs and the partitioning of energy between these organs, a suitable strategy can be devised for the treatment of chronic obesity.

Polymorphisms in the gene encoding sterol regulatory element-binding factor-1c are associated with type 2 diabetes

“…Furthermore, insulin increases SREBF1c mRNA in skeletal muscle and SREBF1c levels in adipose tissue [7,[12][13][14]. Given the mediating role of SREBF1c in the nutritionally and insulinregulated transcription of genes involved in tricacylglycerol and fatty acid synthesis, SREBF1c may underlie the mechanisms that lead to lipotoxicity [1]. The SREBF1c gene can therefore be considered as a good candidate for type 2 diabetes.…”

“…Lipotoxicity in peripheral tissues, which is promoted by defective adipose tissue, could be the link between obesity, insulin resistance and type 2 diabetes [1].…”

Basal lipolysis, not the degree of insulin resistance, differentiates large from small isolated adipocytes in high-fat fed mice

“…At a more metabolic level, hypertrophic adipocytes may exhibit a reduced capacity to store and retain NEFA, leading to elevated levels of circulating NEFA [3]. In contrast, hyperplastic adipocytes may favour the deposition of NEFA and thus protect other tissues such as liver and skeletal muscle from lipotoxicity by sequestering NEFA away from them [3].…”

“…At a more metabolic level, hypertrophic adipocytes may exhibit a reduced capacity to store and retain NEFA, leading to elevated levels of circulating NEFA [3]. In contrast, hyperplastic adipocytes may favour the deposition of NEFA and thus protect other tissues such as liver and skeletal muscle from lipotoxicity by sequestering NEFA away from them [3]. In this regard, treatment with thiazolidinediones has been shown to increase cellularity in adipose tissue by promoting pre-adipocyte differentiation and inducing apoptosis of large adipocytes, resulting in smaller and more insulin-sensitive adipocytes [4].…”

Adipogenesis and lipotoxicity: role of peroxisome proliferator-activated receptor γ (PPARγ) and PPARγcoactivator-1 (PGC1)

“…Cytokines produced by these adipocytes or macrophages may directly antagonise insulin signalling 3,4 . The second mechanism suggests that metabolic changes in adipocytes decrease their capacity to store lipid, facilitating the outflow of lipid into other organs [5][6][7][8] . When the amount of fuel entering these organs exceeds the organs oxidative or storage capacity, a toxic response known as lipotoxicity is induced with the formation of metabolites that inhibit insulin action.…”