Nutritional and Pharmacological Strategies to Modulate White Adipose Tissue Physiology in the Management of Insulin Resistance and Type 2 Diabetes
White adipose tissue (WAT) is a crucial tissue implicated in metabolic health due to its roles in lipid handling and inflammation. In obesity, WAT fatty acid uptake and release is deregulated and released cytokines are primarily pro-inflammatory. Peroxisome proliferator-activated receptor-γ (PPARγ) and transforming growth factor-β (TGF-β) and its downstream Sma- and mothers against decapentaplegic (MAD)-related proteins (SMAD) cascade have been implicated in WAT physiology and whole-body carbohydrate and lipid homeostasis. However, the relationship between TGF-β/SMAD, PPARγ and WAT physiology remains to be elucidated. Rosiglitazone (ROSI), a PPARγ agonist, and resveratrol (RSV) are used to prevent and treat metabolic disorders and type 2 diabetes. However, the use of ROSI in clinical settings is limited due to its adverse side effects. In addition, it remains unclear whether RSV induces metabolic benefits in humans. To date, the roles of RSV, alone or with ROSI, on WAT lipid handling and inflammation have yet to be examined. This thesis sought to investigate the effects of RSV and ROSI, individually and in combination, in rodent WAT in vivo and ex vivo and in human WAT in vitro. In the first study of this thesis, chronic RSV supplementation improved glucose homeostasis in diabetic rodents, which was associated with depot-specific stimulation of WAT glyceroneogenesis, mitochondrial biogenesis and adiponectin secretion. In the second study of this thesis, ROSI-induced adipogenesis in Zucker diabetic fatty rats was associated with depot-specific dephosphorylation and deactivation of SMAD2 and SMAD3 along with increased protein content of inhibitory SMAD7 and SMAD ubiquitination regulatory factor 2 (SMURF2). Finally, the concomitant treatment of cultured WAT from morbidly obese patients with RSV and ROSI additively increased the expression of the glyceroneogenic genes PDK4 and PEPCK. Taken together, this thesis highlights that RSV and ROSI, individually and in combination, favourably modulate lipid handling in WAT from rodents and humans in a depot-specific manner. In addition, it suggests that PPARγ agonism inhibits TGF-β/SMAD signalling, which is associated with WAT adipogenesis. Finally, these data support the concept of a combined pharmacological and nutraceutical approach to prevent and treat metabolic pathologies, which may improve the tolerability of current anti-diabetic therapies.