The growing focus on brown adipocytes has spurred an interest in their potential benefits for metabolic diseases. Brown and beige (or brite) adipocytes express high levels of uncoupling protein 1 (Ucp1) to dissipate heat instead of generating ATP. Ucp1 induction by stimuli including cold, exercise, and diet increases nonshivering thermogenesis, leading to increased energy expenditure and prevention of obesity. Recently, studies in adipocytes have indicated the existence of functional Ucp1-independent thermogenic regulators. Furthermore, substrate cycling involving creatine metabolites, cold-induced N-acyl amino acids, and oxidized lipids in white adipocytes can increase energy expenditure in the absence of Ucp1. These studies emphasize the need for a better understanding of the mechanisms governing energy expenditure in adipocytes and their potential applications in the prevention of human obesity and metabolic diseases. KEYWORDS adipocyte, energy expenditure, obesity, Ucp1 1 | GLOBAL EPIDEMIC OF OBESITY By 2030, approximately 57.8% (3.3 billion) of the adult population throughout the world could be obese or overweight. 1 The global epidemic of obesity could cause various diseases, including liver disease, diabetes, cardiovascular disease, and cancer. 2 Obesity is characterizedby an accumulation of excess energy as triglycerides and occurs when the overall energy intake surpasses energy expenditure. Appetite suppression by pharmacological means is considered to be one approach to prevent obesity. However, this treatment has several side effects, most of which are related to the nervous system. 3 Inhibiting the absorption of dietary fat in the intestine is another approach. Unfortunately, it is associated with diarrhea, headache, and nausea 4,5 Recent efforts have focused on the manipulation of thermogenic brown adipocytes as a means to increase energy expenditure and develop a promising new strategy for ameliorating obesity and metabolic diseases. [6][7][8] In particular, the discovery of active brown adipocytes in the human body encouraged increases in energy expenditure as an excellent alternative for treating human obesity and metabolic diseases. 9-11 Here, we review thermogenesis in adipocytes and further discuss the importance of functional uncoupling protein 1 (Ucp1)dependent and Ucp1-independent thermogenic stimulators (Table 1).
Sesamol found in sesame oil has been shown to ameliorate obesity by regulating lipid metabolism. However, its effects on energy expenditure and the underlying molecular mechanism have not been clearly elucidated. In this study, we show that sesamol increased the uncoupling protein 1 (Ucp1) expression in adipocytes. The administration of sesamol in high-fat diet (HFD)-fed mice prevented weight gain and improved metabolic derangements. The three-week sesamol treatment of HFD-fed mice, when the body weights were not different between the sesamol and control groups, increased energy expenditure, suggesting that an induced energy expenditure is a primary contributing factor for sesamol’s anti-obese effects. Consistently, sesamol induced the expression of energy-dissipating thermogenic genes, including Ucp1, in white adipose tissues. The microarray analysis showed that sesamol dramatically increased the Nrf2 target genes such as Hmox1 and Atf3 in adipocytes. Moreover, 76% (60/79 genes) of the sesamol-induced genes were also regulated by tert-butylhydroquinone (tBHQ), a known Nrf2 activator. We further verified that sesamol directly activated the Nrf2-mediated transcription. In addition, the Hmox1 and Ucp1 induction by sesamol was compromised in Nrf2-deleted cells, indicating the necessity of Nrf2 in the sesamol-mediated Ucp1 induction. Together, these findings demonstrate the effects of sesamol in inducing Ucp1 and in increasing energy expenditure, further highlighting the use of the Nrf2 activation in stimulating thermogenic adipocytes and in increasing energy expenditure in obesity and its related metabolic diseases.
Cold-induced norepinephrine activates β3-adrenergic receptors (β3-AR) to stimulate the kinase cascade and cAMP-response element-binding protein, leading to the induction of thermogenic gene expression including uncoupling protein 1 (Ucp1). Here, we showed that stimulation of the β3-AR by its agonists isoproterenol and CL316,243 in adipocytes increased the expression of Ucp1 and Heme Oxygenase 1 (Hmox1), the principal Nrf2 target gene, suggesting the functional interaction of Nrf2 with β3-AR signaling. The activation of Nrf2 by tert-butylhydroquinone and reactive oxygen species (ROS) production by glucose oxidase induced both Ucp1 and Hmox1 expression. The increased expression of Ucp1 and Hmox1 was significantly reduced in the presence of a Nrf2 chemical inhibitor or in Nrf2-deleted (knockout) adipocytes. Furthermore, Nrf2 directly activated the Ucp1 promoter, and this required DNA regions located at −3.7 and −2.0 kb of the transcription start site. The CL316,243induced Ucp1 expression in adipocytes and oxygen consumption in obese mice were partly compromised in the absence of Nrf2 expression. These data provide additional insight into the role of Nrf2 in β3-AR-mediated Ucp1 expression and energy expenditure, further highlighting the utility of Nrf2-mediated thermogenic stimulation as a therapeutic approach to diet-induced obesity. [BMB Reports 2021; 54(8): 419-424]
The phytochemical oxyresveratrol has been shown to exert diverse biological activities including prevention of obesity. However, the exact reason underlying the anti-obese effects of oxyresveratrol is not fully understood. Here, we investigated the effects and mechanism of oxyresveratrol in adipocytes and high-fat diet (HFD)-fed obese mice. Oxyresveratrol suppressed lipid accumulation and expression of adipocyte markers during the adipocyte differentiation of 3T3-L1 and C3H10T1/2 cells. Administration of oxyresveratrol in HFD-fed obese mice prevented body-weight gains, lowered adipose tissue weights, improved lipid profiles, and increased glucose tolerance. The anti-obese effects were linked to increases in energy expenditure and higher rectal temperatures without affecting food intake, fecal lipid content, and physical activity. The increased energy expenditure by oxyresveratrol was concordant with the induction of thermogenic genes including Ucp1, and the reduction of white adipocyte selective genes in adipose tissue. Furthermore, Foxo3a was identified as an oxyresveratrol-induced gene and it mimicked the effects of oxyresveratrol for induction of thermogenic genes and suppression of white adipocyte selective genes, suggesting the role of Foxo3a in oxyresveratrol-mediated anti-obese effects. Taken together, these data show that oxyresveratrol increases energy expenditure through the induction of thermogenic genes in adipose tissue and further implicates oxyresveratrol as an ingredient and Foxo3a as a molecular target for the development of functional foods in obesity and metabolic diseases.
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