The natural compound rutaecarpine promotes white adipocyte browning through activation of the AMPK-PRDM16 axis.

The prevalence of obesity is increasing globally and is associated with many metabolic disorders, such as type 2 diabetes and cardiovascular diseases. In recent years, a number of studies suggest that promotion of white adipose browning represents a promising strategy to combat obesity and its related metabolic disorders. The aim of this study was to identify compounds that induce adipocyte browning and elucidate their mechanism of action. Among the 500 natural compounds screened, a small molecule named Rutaecarpine, was identified as a positive regulator of adipocyte browning both in vitro and in vivo. KEGG pathway analysis from RNA-seq data suggested that the AMPK signaling pathway was regulated by Rutaecarpine, which was validated by Western blot analysis. Furthermore, inhibition of AMPK signaling mitigated the browning effect of Rutaecaripine. The effect of Rutaecaripine on adipocyte browning was also abolished upon deletion of Prdm16, a downstream target of AMPK pathway. In collusion, Rutaecarpine is a potent chemical agent to induce adipocyte browning and may serve as a potential drug candidate to treat obesity.

The natural compound, formononetin, extracted from Astragalus membranaceus increases adipocyte thermogenesis by modulating PPARγ activity.

BACKGROUND AND PURPOSE: Increasing energy expenditure through adipocyte thermogenesis is generally accepted as a promising strategy to mitigate obesity and its related diseases. However, few clinically effective and safe agents are known to promote adipocyte thermogenesis. In this study, 20 traditional Chinese herbal medicines were screened to examine whether they induced adipocyte thermogenesis. EXPERIMENTAL APPROACH: The effects of Chinese herbal medicines or components isolated from extracts of A. membranaceus, on adipocyte thermogenesis were analysed by assessing expression of uncoupling protein 1 (UCP1) by qPCR. Eight-week-old C57BL6/J male mice were fed a high-fat diet for 8 weeks and then randomized to two groups treated with vehicle or formononetin for another 8 weeks. Glucose tolerance tests and staining of adipose tissue with haematoxylin and eosin were carried out. Whole-body oxygen consumption was measured with an open-circuit indirect calorimetry system. KEY RESULTS: Extracts of A. membranaceus increased expression of Ucp1 in primary cultures of mouse adipocytes. Formononetin was the only known component of A. membranaceus extracts to increase adipocyte Ucp1 expression. Diet-induced obese mice treated with formononetin gained less weight and showed higher energy expenditure than untreated mice. In addition, formononetin binds directly with PPARγ. CONCLUSIONS AND IMPLICATION: Taken together, our study demonstrates that the Chinese herbal medicine from A. membranaceus and its constituent formononetin have the potential to reduce obesity and associated metabolic disorders. Our results suggest that formononetin regulates adipocyte thermogenesis as a non-classical PPARγ agonist.

Low omega-6/omega-3 polyunsaturated fatty acid ratios reduce hepatic C-reactive protein expression in apolipoprotein E-null mice.

OBJECTIVE: Expression characteristics of C-reactive protein (CRP) for the omega-6/omega-3 polyunsaturated fatty acid (PUFA) ratios have not been evaluated in the well-qualified experimental atherosclerotic mouse model. This work focused on characteristics of CRP expression in the liver of apolipoprotein E-null (apoE(-/-)) mice influenced by omega-6/omega-3 PUFA ratios. METHODS: Varying ratios of omega-6/omega-3 PUFAs (group 1, 1.28; group 2, 5.03; group 3, 9.98; and group 4, 68.26, respectively) on hepatic and aortic CRP expressions were assessed in male apoE(-/-) mice fed a diet containing 5% (w/w) experimental fat for 6 wk. Hepatic peroxisome proliferator-activated receptor-gamma mRNA abundance, hepatic interleukin (IL)-6 protein level, atherosclerotic lesions, and serum cytokines including IL-1beta, IL-6, and tumor necrosis factor-alpha were examined. RESULTS: As the dietary ratio of omega-6/omega-3 fatty acids ascended, so did the expression of hepatic and aortic CRP and hepatic IL-6 protein. However, peroxisome proliferator-activated receptor-gamma mRNA level had a tendency to decrease. Serum IL-1beta, IL-6, and tumor necrosis factor-alpha levels did not show a statistical difference among the mice fed the four ratios of the omega-6/omega-3 PUFA diet. The group 4 mice developed a significant increase in atherosclerotic lesions compared with the other groups. CONCLUSION: The results indicated that low ratios of omega-6/omega-3 PUFAs (1.28-9.98) downregulated the hepatic and aortic CRP expressions and reduced aortic en face lesions in apoE(-/-) mice compared with the high ratio of the omega-6/omega-3 PUFA diet.

High dietary n-6/n-3 PUFA ratio promotes HDL cholesterol level, but does not suppress atherogenesis in apolipoprotein E-null mice 1.

AIM: Dietary fatty acids affect atherogenesis, which was presumed to be partly related to HDL cholesterol (HDL-C) metabolism. The major aim of the work was to analyze various ratios of n-6/n-3 PUFA diets on HDL-C metabolism in apolipoprotein E-null (apoE(-/-)) mice, which have similar symptoms to human type III familial hyperlipoproteinemia. METHODS: Two-month-old male apoE(-/-) mice were fed four types of n-6/n-3 PUFA diet (group 1, 1.28; group 2, 5.03; group 3, 9.98 and group 4, 68.26) and control diet, respectively, for 6 weeks. With respect to serum apolipoprotein (apo) A-I concentration, lecithin-cholesterol acyltransferase (LCAT) activity and mRNA abundance of genes involved in HDL-C metabolism in the liver were analyzed. RESULTS: Group 4 diet significantly increased the plasma HDL-C and apoA-I concentrations compared with other groups. LCAT activity in serum increased with decreased ratios of n-6/n-3 PUFA. As the dietary ratio of n-6/n-3 fatty acids increased, so did mRNA levels of hepatic apoA-I, scavenger receptor B class-1 (SR-B1), LCAT, ATP binding cassette transporter A1 (ABCA1), ABCG1 and liver X receptor alpha (LXRalpha). ApoA-II mRNA level, however, had a tendency to fall. Group 4 diet increased apoA-I and ABCA1 and decreased apoA-II transcriptional levels, whereas group 1 diet decreased mRNA levels of apoA-I, LCAT, SR-B1 and ABCG1. CONCLUSION: Our data indicated that a high ratio of n-6/n-3 PUFA increased the serum HDL-C level, but did not effectively suppress atherogenesis in apoE(-/-) mice. The elevated HDL-C level is possibly due to up-regulated hepatic apoA-I and ABCA1 with suppression of apoA-Ii expression.