Obesity is characterized by the expansion of the white adipose tissue (WAT), which is associated with the risk of suffering from metabolic diseases including type 2 diabetes mellitus (T2DM). Adequate rates of adipocyte differentiation (adipogenesis) promote healthy WAT expansion and metabolic homeostasis. Healthy WAT expansion buffers lipids, preventing ectopic lipid accumulation in organs such as the muscle and liver. On the other hand, pathological WAT expansion, characterized by adipocyte hypertrophy, hypoxia, inflammation and fibrosis, leads to WAT dysfunction and metabolic decline, including hyperlipidaemia and hyperglycaemia.
Oxylipins are bioactive lipid mediators that regulate adipogenesis, but little is known about the specific role of the epoxyganase (CytochromeP450) pathway during adipogenesis. In this thesis, we characterized the major CYP2J epoxygenases and established their contribution to adipogenesis in human and rat adipocyte precursor (AP) cells. We first report that inactivation of CYP2J induces spontaneous adipocyte differentiation.
We next sought to understand the consequences of CYP2J depletion and spontaneous adipogenesis in whole-body metabolic homeostasis. We used two obesogenic models (Cafeteria diet and ageing) in rats lacking the main WAT epoxygenase (Cyp2j4). The Cyp2j4-/- rats showed relatively higher rates of adipogenesis at basal conditions, which caused increased adiposity and WAT dysfunction upon obesogenic conditions. WAT dysfunction was characterized by adipocyte hypertrophy, macrophage infiltration, interstitial collagen deposition, and elevated pro-inflammatory oxylipin levels (i.e. prostaglandins). Moreover, Cyp2j4-/- rats showed exacerbated hepatic lipid accumulation and insulin resistance, causing unrestrained hepatic glucose production, a hallmark of T2DM.
WAT dysfunctional features, including increased macrophage infiltration and collagen deposition, were conserved in obese patients with T2DM when compared to obese but non-T2DM patients. Prostaglandins were also increased in the WAT of T2DM patients. In humans and rats, the association between macrophage infiltration, collagen deposition and prostaglandin levels suggested macrophages as regulators of WAT collagen deposition, possibly through prostaglandin secretion. Therefore, we proposed an alternative usage of oxylipin precursors towards prostaglandin biosynthesis and metabolism in WAT dysfunction, unveiling prostaglandins as a potential therapeutic target to treat WAT inflammation and fibrosis.
Together these results elucidate the role of epoxygenases and prostaglandins in regulating adipocyte differentiation, WAT expansion and inflammation.