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. 2022 Apr 13;15(4):469.
doi: 10.3390/ph15040469.

Rutaecarpine Promotes Adipose Thermogenesis and Protects against HFD-Induced Obesity via AMPK/PGC-1α Pathway

Dandan Chen  1   2 , Yanan Duan  2 , Shuxiang Yu  1 , Xinwen Zhang  2 , Ni Li  2 , Jingya Li  2
Affiliations

Rutaecarpine Promotes Adipose Thermogenesis and Protects against HFD-Induced Obesity via AMPK/PGC-1α Pathway

Dandan Chen et al. Pharmaceuticals (Basel). .

Abstract

Pharmacological activation of adaptive thermogenesis to increase energy expenditure is considered to be a novel strategy for obesity. Peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α), which serves as an inducible co-activator in energy expenditure, is highly expressed in brown adipose tissues (BAT). In this study, we found a PGC-1α transcriptional activator, natural compound rutaecarpine (Rut), which promoted brown adipocytes mitochondrial biogenesis and thermogenesis in vitro. Chronic Rut treatment reduced the body weight gain and mitigated insulin sensitivity through brown and beige adipocyte thermogenesis. Mechanistic study showed that Rut activated the energy metabolic pathway AMP-activated protein kinase (AMPK)/PGC-1α axis, and deficiency of AMPK abolished the beneficial metabolic phenotype of the Rut treatment in vitro and in vivo. In summary, a PGC-1α transcriptional activator Rut was found to activate brown and beige adipose thermogenesis to resist diet-induced obesity through AMPK pathway. Our findings serve as a further understanding of the natural compound in adipose tissue and provides a possible strategy to combat obesity and related metabolic disorders.

Keywords: AMP-activated protein kinase; adipocytes; browning; obesity; peroxisome-proliferator-activated receptor γ co-activator-1α; rutaecarpine; thermogenesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Rut increases expression of PGC-1α and drives the thermogenesis program. (A) The screening result of Rut in activating PGC-1α. (B) Effect of Rut on activating PGC-1α in C3H10-T1/2. (C) RT-qPCR analysis of genes indicated in C3H10-T1/2. (D) Expressions of protein indicated in C3H10-T1/2 treated by Rut for 24 h. (E–G) Relative protein level of PGC-1α (E), UCP1 (F) and NRF2 (G) compared to β-actin. n = 3 per group. Data are presented as the means ±SEM. * p < 0.05, ** p < 0.01, *** p < 0.001, Rut groups versus vehicle group by one-way ANOVA.
Figure 2
Figure 2
Rut enhances thermogenic program and increases mitochondrial respiration of primary brown and beige adipocytes. (A) Expression of thermogenic genes in differentiated primary brown adipocytes (BAT-SVF). (B) UCP1 and PGC-1α protein expression level in BAT-SVF. (C) OCR in differentiated primary brown adipocytes on basal condition, in the presence of 2 μM oligomycin, 1 μM FCCP or 1 μM rotenone/antimycin. (D) Statistical graphs of basal and uncoupled respiration in BAT-SVF. (E) Expression of thermogenic and fuel consuming genes in functional primary subcutaneous adipocytes (Sub-SVF). (F) Western blot analysis of PGC-1α, UCP1 protein levels in Sub-SVF. (G) The testing of OCR in Rut-treated Sub-SVF. (H) Statistical values of basal and uncoupled respiration in Sub-SVF. n = 3 per group. Data are presented as the means ±SEM. * p < 0.05, ** p < 0.01, Rut groups versus vehicle group by one-way ANOVA.
Figure 3
Figure 3
Rut restrains the weight gain of HFD-fed mice and ameliorates insulin resistance. (A) Body weights were recorded each week after Rut treatment. (B) Tissues were collected and weighted. (C) Proportion of body composition of mice. (D) Representative hematoxylin and eosin staining (HE staining) from interscapular BAT and inguinal WAT sections of HFD-fed mice after 8 weeks of Rut treatment. Scale bar, 50 µm. (E,F) Quantification of adipocyte area of iBAT (E) and iWAT (F). (G) Blood glucose curves during testing of oral glucose tolerance (GTT). (H) Area under curve (AUC) of GTT. (I) Blood glucose levels were plotted in insulin tolerance test (ITT). (J) Analysis of AUC during ITT. n = 6 per group. Data are presented as the means ±SEM. Student’s t-test. * p < 0.05, ** p < 0.01, *** p < 0.001 compared with the indicated control group.
Figure 4
Figure 4
Rut promotes heat generation and energy expenditure in HFD-fed mice. (A) Monitoring of oxygen consumption (VO2). (B) Average O2 consumption. (C) Analysis of energy expenditure (EE) in 24 h and after administration of CL316,243. (D) Average energy expenditure. (E) Rectal temperatures of HFD mice were recorded every hour after transition to 4 °C from 22 °C. (F) Representative infrared thermal images of HFD-fed mice treated with vehicle or Rut after 6 h of exposure to 4 °C. (G) Quantification of the interscapular BAT skin temperatures of HFD mice. (H,I) RT-qPCR analysis of thermogenic genes in iBAT (H) and iWAT (I) from HFD mice. (J,K) Western blot analysis of proteins indicated in iBAT (J) and iWAT (K). n = 4–6 per group. Data are presented as the means ±SEM. Student’s t-test. * p < 0.05, ** p < 0.01 compared with the indicated control group.
Figure 5
Figure 5
Thermogenic effects induced by Rut treatment are ablated in thermoneutral conditions. (A,B) Body weights of HFD-fed mice treated with vehicle or Rut housed at 22 °C (A) or 30 °C (B). (C) Rectal temperature changes of mice were recorded every hour during cold stimuli. (D) Representative infrared thermal images of mice after cold exposure. (E) Quantification of interscapular BAT skin temperatures of 22 °C or 30 °C mice treated with vehicle or Rut. (F,G) The changes in O2 consumption of mice acclimated at 22 °C (F) and 30 °C (G). (H) Assessment of average O2 consumption. n = 5 per group. Data are presented as the means ±SEM. * p < 0.05, ** p < 0.01, Rut group versus vehicle group; # p < 0.05, ## p < 0.01, ### p < 0.001, 30 °C group versus 22 °C group by Student’s t-test.
Figure 6
Figure 6
Rut stimulates thermogenic program via AMPK/PGC-1α pathway. (A) Expression of PGC-1α and UCP1 protein by siRNA against PGC-1α. (B,C) Relative protein level of PGC-1α (B) and UCP1 (C) compared to β-actin. (D) The mRNA level of Pgc-1α and Ucp1 after blockage of PGC-1α. (E) Expression of p-AMPK, AMPK, p-ACC and ACC protein in C3H10-T1/2 treated by Rut. (F) Expression of PGC-1α and UCP1 protein in C3H10-T1/2 with siRNA against AMPK and Rut treatment. (G,H) Relative protein level of PGC-1α (G) and UCP1 (H) compared to β-actin. (I) The mRNA level of Pgc-1α and Ucp1 after silence of AMPK. n = 3 per group. Data are presented as the means ±SEM. * p < 0.05, ** p < 0.01, Rut group versus vehicle group; # p < 0.05, ## p < 0.01, ### p < 0.001, siRNA group versus control group by Student’s t-test.
Figure 7
Figure 7
Thermogenic effects induced by Rut are attenuated by absence of AMPK. (A) Body weight of the indicated mice group. (B) Rectal temperature changes of four groups mice were recorded at 4 °C. (C) Representative infrared thermal images of floxed or AKO mice treated with vehicle or Rut after 6 h of exposure to 4 °C. (D) Statistical graphs of interscapular BAT skin heat. (E) Glucose levels were plotted versus times post insulin injection. (F) Analysis of AUC during ITT. (G) Testing of O2 consumption. (H) Average of O2 consumption under basal and CL316,243 stimulation conditions. (I) Assessment of EE. (J) Average of EE under basal and CL316,243 stimulation conditions. (K,L) Expression level of thermogenic genes by RT-qPCR analysis in iBAT (K) and iWAT (L). (M,N) Western blot analysis of AMPK, PGC-1α and UCP1 expression level in iBAT (M) and iWAT (N) of different groups mice. n = 5–6 per group. Data are presented as the means ±SEM. Student’s t-test. * p < 0.05, ** p < 0.01, *** p < 0.001, Rut group versus vehicle group; # p < 0.05, ## p < 0.01, ### p < 0.001, AKO group versus floxed group.
Figure 8
Figure 8
Graphical abstract. In this study, we revealed the effects of rutaecarpine (Rut) on thermogeneis and weight management. Rut can reduce adiposity, improve insulin resistance and increase respiratory activity in mice with HFD-induced obesity. The mechanism of the effects of Rut involved AMPK/PGC-1α pathway, and we demonstrated that AMPK deficiency in adipose tissue suppressed the upregulation of thermogenic markers and beneficial metabolic effects in Rut-treated mice.
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