Abstract
Stimulation of white adipose tissue (WAT) browning is considered as a potential approach to treat obesity and metabolic diseases. Our previous studies have shown that phytochemical butein can stimulate WAT browning through induction of Prdm4 in adipocytes. Here, we investigated the effects of butein on diet-induced obesity and its underlying molecular mechanism. Treatment with butein prevented weight gains and improved metabolic profiles in diet-induced obese mice. Butein treatment groups also displayed higher body temperature, increased energy expenditure, and enhanced expression of thermogenic genes in adipose tissue. Butein also suppressed body weight gains and improved glucose and insulin tolerance in mice housed at thermoneutrality (30 °C). These effects were associated with adipose-selective induction of Prdm4, suggesting the role of Prdm4 in butein-mediated anti-obese effects. To directly assess the in vivo role of Prdm4, we generated aP2-Prdm4 transgenic mouse lines overexpressing Prdm4 in adipose tissues. Adipose-specific transgenic expression of Prdm4 recapitulated the butein’s actions in stimulating energy expenditure, cold tolerance, and thermogenic gene expression, resulting in prevention of obesity and improvement of metabolism. Mechanistically, direct inhibition of PI3Kα activity followed by selective suppression of its downstream Akt1 mirrored butein’s effect on Ucp1 expression and oxygen consumption. In addition, effects of butein were completely abolished in Akt1 KO mouse embryonic fibroblasts. Together, these studies demonstrate the role of butein in obesity and metabolic diseases, further highlighting that adipose PI3Kα–Akt1–Prdm4 axis is a regulator of energy expenditure.
Highlights
Increased calorie intake with less energy expenditure has led to an epidemic of obesity with subsequent development of various metabolic diseases, including diabetes, hypertension, cardiovascular diseases, and increased cancer risk[1,2,3]
Expression levels of thermogenic adipocyte markers Ucp[1], Prdm[16], Cox8b, and Cidea were significantly induced in inguinal White adipose tissue (WAT) compared with those in the control group (Supplementary Figure S1)
Increase of brown adipose tissue (BAT)-like activity in WAT in human upon cold acclimation can increase energy expenditure and reduce body fat mass[8,12,45]. These observations led to the notion that activation of BAT might be considered as a new strategy for counteracting obesity and its associated metabolic derangements
Summary
Increased calorie intake with less energy expenditure has led to an epidemic of obesity with subsequent development of various metabolic diseases, including diabetes, hypertension, cardiovascular diseases, and increased cancer risk[1,2,3]. Recent studies have revealed the existence of BAT in adult humans and the association between BAT activity and lower body mass in different populations, bringing new attention to brown fat as a therapeutic target for treating metabolic diseases[8,9,10,11,12]. Other thermogenic cells as clusters of adipocytes have been found in WAT These cells are referred to as beige adipocytes, brite (brown in white), or brown-like adipocytes[13,14,15]. Both brown and beige adipocytes are characterized by high mitochondrial contents and are believed to exhibit similar functions in energy metabolism[6,13,16]. The identification of beige-specific cell surface markers and different origins of these adipocytes indicate that beige cells are unique adipocytes, different from classical WAT or BAT17,18
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