Public Health Nutrition: 10(10A), 1132–1137 DOI: 10.1017/S1368980007000614 Adipogenesis and lipotoxicity: role of peroxisome proliferator- activated receptor g (PPARg) and PPARgcoactivator-1 (PGC1) Gema Medina-Gomez*, Sarah Gray and Antonio Vidal-Puig 1 Department of Clinical Biochemistry and Medicine, University of Cambridge, Box 232, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QR, UK Submitted December 2006: Accepted April 2007 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 non- adipose 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 physio- logical 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. Keywords Peroxisome proliferator activated receptors (PPARs) Obesity Lipotoxicity Adipogenesis PGC1 b-oxidation Fat mass is determined by a dynamic equilibrium between food intake and energy expenditure. Disruption of this balance leads to obesity, a multifactorial disease that involves an increase in adipose tissue mass. An adipocentric view considers obesity as a major risk factor for the development of insulin resistance, hyperglycaemia (with or without type 2 diabetes), hyperlipidemia and hypertension, collectively referred to as the metabolic syndrome. These inter-related disorders predispose patients to a variety of cardiovascular conditions that lead to high risk of heart attack and stroke. The clinical observation that not every obese individual develops these problems suggests that is not a direct effect of the absolute amount of fat accumulated. Many obese patients are remarkably metabolically healthy despite massive accumulation of fat, whereas others who are only moderately obese develop the full metabolic syndrome. Therefore, there are indications that adipose tissue expandability may be an important factor deter- mining the metabolic complications associated with obesity 1,2 . It has been suggested that the link between the expan- sion of adipose tissue and these co-morbidities is insulin resistance, a state characterised by an impaired response to insulin in peripheral tissues. Two non-exclusive mech- anisms have been proposed to explain how expansion of adipose tissue affects insulin sensitivity. The first one sug- gests that excessive accumulation of fat is associated with a chronic state of inflammation characterised by increased cytokine production by adipocytes and/or the macrophages infiltrating adipose tissue. Cytokines produced by these adipocytes or macrophages may directly antagonise *Corresponding author: Email mgm28@cam.ac.uk r The Authors 2007