Phytochemicals as novel agents for the induction of browning in white adipose tissue

Obesity and its associated metabolic syndrome continue to be a health epidemic in westernized societies and is catching up in the developing world. Despite such increases, little headway has been made to reverse adverse weight gain in the global population. Few medical options exist for the treatment of obesity which points to the necessity for exploration of anti-obesity therapies including pharmaceutical and nutraceutical compounds. Defects in brown adipose tissue, a major energy dissipating organ, has been identified in the obese and is hypothesized to contribute to the overall metabolic deficit observed in obesity. Not surprisingly, considerable attention has been placed on the discovery of methods to activate brown adipose tissue. A variety of plant-derived, natural compounds have shown promise to regulate brown adipose tissue activity and enhance the lipolytic and catabolic potential of white adipose tissue. Through activation of the sympathetic nervous system, thyroid hormone signaling, and transcriptional regulation of metabolism, natural compounds such as capsaicin and resveratrol may provide a relatively safe and effective option to upregulate energy expenditure. Through utilizing the energy dissipating potential of such nutraceutical compounds, the possibility exists to provide a therapeutic solution to correct the energy imbalance that underlines obesity

Plac8 is required for white adipocyte differentiation in vitro and cell number control in vivo.

Plac8 belongs to an evolutionary conserved family of proteins, mostly abundant in plants where they control fruit weight through regulation of cell number. In mice, Plac8 is expressed both in white and brown adipose tissues and we previously showed that Plac8(-/-) mice develop late-onset obesity, with abnormal brown fat differentiation and reduced thermogenic capacity. We also showed that in brown adipocytes, Plac8 is an upstream regulator of C/EBPβ expression. Here, we first assessed the role of Plac8 in white adipogenesis in vitro. We show that Plac8 is induced early after induction of 3T3-L1 adipocytes differentiation, a process that is prevented by Plac8 knockdown; similarly, embryonic fibroblasts obtained from Plac8 knockout mice failed to form adipocytes upon stimulation of differentiation. Knockdown of Plac8 in 3T3-L1 was associated with reduced expression of C/EBPβ, Krox20, and Klf4, early regulators of the white adipogenic program, and we show that Plac8 could transactivate the C/EBPβ promoter. In vivo, we show that absence of Plac8 led to increased white fat mass with enlarged adipocytes but reduced total number of adipocytes. Finally, even though Plac8(-/-) mice showed impaired thermogenesis due to brown fat dysfunction, this was not associated with changes in glycemia or plasma free fatty acid and triglyceride levels. Collectively, these data indicate that Plac8 is an upstream regulator of C/EBPβ required for adipogenesis in vitro. However, in vivo, Plac8 is dispensable for the differentiation of white adipocytes with preserved fat storage capacity but is required for normal fat cell number regulation

PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance

Obesity is associated with a chronic low-grade inflammation, and specific antiinflammatory interventions may be beneficial for the treatment of type 2 diabetes and other obesity-related diseases. The lipid kinase PI3Kγ is a central proinflammatory signal transducer that plays a major role in leukocyte chemotaxis, mast cell degranulation, and endothelial cell activation. It was also reported that PI3Kγ activity within hematopoietic cells plays an important role in obesity-induced inflammation and insulin resistance. Here, we show that protection from insulin resistance, metabolic inflammation, and fatty liver in mice lacking functional PI3Kγ is largely consequent to their leaner phenotype. We also show that this phenotype is largely based on decreased fat gain, despite normal caloric intake, consequent to increased energy expenditure. Furthermore, our data show that PI3Kγ action on diet-induced obesity depends on PI3Kγ activity within a nonhematopoietic compartment, where it promotes energetic efficiency for fat mass gain. We also show that metabolic modulation by PI3Kγ depends on its lipid kinase activity and might involve kinase-independent signaling. Thus, PI3Kγ is an unexpected but promising drug target for the treatment of obesity and its complications