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

Abstract

Obesity is characterised by an increase in the adipose deposits, resulting from an imbalance between food intake and energy expenditure. When expansion of the adipose tissue reaches its maximum limit, as in obesity, fat accumulates in nonadipose tissues such as liver, heart, muscle and pancreas, developing a toxic response known as lipotoxicity, a condition that promotes the development of insulin resistance and other metabolic complications. Thus, the lipotoxic state may contribute to the increased risk of insulin resistance, diabetes, fatty liver and cardiovascular complications associated with obesity.We are interested in studying adipose tissue, specifically how mechanisms of adipogenesis and remodelling of adipose tissue, in terms of size and function of the adipocytes, could be considered a strategy to increase the capacity for lipid storage and prevent lipotoxicity. The peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors that regulate energy balance by promoting either energy deposition or energy dissipation. Under normal physiological conditions, PPARg is mainly expressed in adipose tissue and regulates diverse functions such as the development of fat cells and their capacity to store lipids. The generation of PPARg knockout mice, either tissue specific or isoform specific, has provided new models to study PPARg's role in adipose tissue differentiation and function and have highlighted the essential role of PPARg in adipogenesis and lipogenesis.A second strategy to prevent lipotoxicity is to increase the capacity of tissues to oxidise fatty acids. PPARgcoactivator-1a is a coactivator of PPARg that induces the expression of genes that promote the differentiation of preadipocytes to brown adipocytes. Recently, it has been implicated in increasing the oxidation of fatty acids via increasing mitochondrial capacity and function, making this co-factor a key candidate for the treatment of lipotoxicity.

Pioglitazone Reduces Vascular Lipid Accumulation in Angiotensin II-Induced Hypertensive Rat

“…Under normal conditions, PPAR is mainly expressed in adipose tissue and regulates various functions, including the development of fat cells and their capacity to store lipids 27) . Because PPAR plays a pivotal role in adipogenesis, its mutation causes a failure of adipogenesis and leads to insuangiotensin II, was also inhibited by pioglitazone.…”

The Role of Altered Lipid Metabolism in Septic Myocardial Dysfunction

“…At present the presence in the myocardial cell of neutral lipid droplets is ascribed to the altered glucose and lipid metabolism and to a mismatch between lipid delivery and oxidation. In normal conditions TG are stored only in adipocytes, under the control of PPAR with minimal presence of lipids in other tissues [231,232]; in this way adipocytes play indirectly a key role in the control of systemic glucose, lipid homeostasis and insulin sensitivity through the regulation of the serum level of FFA. In congenital lipodystrophy, a disease characterized by a decreased capacity of lipid storage in adipose tissue, the non-adipose organs accumulate TG and there is a premature cardiomyopathy [233].…”

Therapeutic targets of brain insulin resistance in sporadic Alzheimer s disease

“…PPARs, including PPAR-γ, regulate energy balance by promoting dissipation or deposition of energy. PPAR-γ-coactivator 1alpha (PGC1-alpha) induces gene expression that promotes differentiation, and increases fatty acid oxidation via expansion of mitochondrial capacity and function (177). PGC1alpha binds to nuclear PPAR-γ, which then enables its interactions with various transcription factors that regulate mitochondrial biogenesis.…”

“…PGC1alpha binds to nuclear PPAR-γ, which then enables its interactions with various transcription factors that regulate mitochondrial biogenesis. In essence, PGC1alpha is an important negative regulator of oxidative stress, mitochondrial dysfunction, lipotoxicity, and insulin resistance (177)(178)(179). The relevance of these data to AD is that genetic deficiencies in PGC1 alpha increase proneness to neurodegeneration (179,180).…”