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. 2015 May 21;161(5):999-1011.
doi: 10.1016/j.cell.2015.05.011.

Treatment of obesity with celastrol

Junli Liu  1 , Jaemin Lee  1 , Mario Andres Salazar Hernandez  1 , Ralph Mazitschek  2 , Umut Ozcan  3
Affiliations

Treatment of obesity with celastrol

Junli Liu et al. Cell. .

Abstract

Despite all modern advances in medicine, an effective drug treatment of obesity has not been found yet. Discovery of leptin two decades ago created hopes for treatment of obesity. However, development of leptin resistance has been a big obstacle, mitigating a leptin-centric treatment of obesity. Here, by using in silico drug-screening methods, we discovered that Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium Wilfordi (thunder god vine) plant, is a powerful anti-obesity agent. Celastrol suppresses food intake, blocks reduction of energy expenditure, and leads to up to 45% weight loss in hyperleptinemic diet-induced obese (DIO) mice by increasing leptin sensitivity, but it is ineffective in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mouse models. These results indicate that Celastrol is a leptin sensitizer and a promising agent for the pharmacological treatment of obesity.

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Figures

Figure 1
Figure 1. Identification of Celastrol as a Potential Anti-Obesity Molecule
(A) Flow chart depicting the process for obtaining gene expression signatures from the liver to identify potential anti-obesity compounds. C57BL/6J mice (left flow chart) or ob/ob mice (middle flow chart) were orally treated with either vehicle or 4-PBA (n=3 for each group) and ob/ob mice injected with Ad-XBP1s or Ad-LacZ (n=3 for each group) (right flow chart). (B) Heat maps representing the selected 50 upregulated (blue) and 50 downregulated (red) genes – vehicle versus 4-PBA from lean mice (left), vehicle versus 4-PBA from ob/ob mice (middle) and Ad-XBP1s versus Ad-LacZ from ob/ob mice (right). Microarray chip probe and the corresponding gene identifiers are listed next to the heat maps. (C) Three dimensional plot of the absolute enrichment scores obtained from CMAP using three different signatures. Each data point represents a small molecule. Blue to red color-codings represent low to high absolute product score. (D) Formula used to calculate absolute enrichment score for individual small molecules in CMAP database. (E) Distribution of the calculated absolute enrichment score of individual small molecules. The red dot represents Celastrol and its chemical structure is shown in the graph. (F) Flow chart depicting the process used to obtain gene expression signatures in the hypothalamus. C57BL/6J mice were fed on either normal chow diet or high fat diet (n=4 for each group) (left flow chart). DIO mice treated with either vehicle, or 4-PBA or with TUDCA (right flow chart). Geometric means of 4-PBA and TUDCA-induced changes in gene expression (RPBA and RTUDCA) were determined to obtain hypothalamic chaperone signature. (G) Heat map representing the selected 50 upregulated and 50 downregulated hypothalamic genes obtained. Left: lean versus DIO. Right: Vehicle versus (4-PBA and TUDCA). (H) Distribution of individual small molecules in CMAP depending on their absolute enrichment scores obtained by analysis of hypothalamic obesity signature (Y-axis: obesity enrichment score) and hypothalamic chaperone signature (X-axis: chaperone enrichment score). (I) Distribution of hypothalamic absolute product scores of individual small molecules obtained from CMAP database. (J) The dot distribution of absolute product scores of the liver and the hypothalamus. Each data point represents an individual small molecule. (K) Distribution of the final scores calculated as a product of liver and hypothalamus absolute product scores. Red dot represents Celastrol (H–K). See also Figure S1.
Figure 2
Figure 2. Celastrol Acts as an Anti-Obesity Agent on High Fat Diet-Induced Obese Mice
High fat-fed obese (DIO) mice (A–F) or 10-week-old C57BL/6J lean mice (G–L) were daily treated with vehicle or Celastrol (100 μg/kg) intraperitoneally (i.p) for three weeks. (A) Body weight (g) (n=5 for each group) and (B) Percent decrease (%) in body weight in DIO mice during the treatment. (C) Three-day average of food intakes (g) of DIO mice during the first week of treatment. Experiments were repeated in more than three independent cohorts. (D) Plasma leptin levels of vehicle (n=8) or Celastrol (n=8; 100 μg/kg)-treated DIO mice during three weeks of treatment. (E–F) Dual energy X-ray absorptiometry (DEXA) scans showing (E) lean mass (g) and (F) fat mass (%) of DIO mice after three weeks of treatment (n=6 per each group). DEXA scans were repeated in more than three independent cohorts. (G) Body weight (g) (n=5 for each group), and (H) percent decrease (%) in body weight of lean mice during the treatment. (I) Three-day average food intakes of the lean mice during the first week of treatment. Experiments in (G–I) were repeated three times. (J) Plasma leptin levels of lean mice after three week of treatment (n=11 for each group). (K) Lean mass (g) and (L) fat mass percent (%) of lean mice after three weeks treatment (n=6 per each group). Error bars are represented as mean ± SEM. p values were determined by two-way ANOVA (A and B) or Student’s t test (*p < 0.05, **p < 0.01, ***p <0.001). See also Figure S2 and S7.
Figure 3
Figure 3. Celastrol Is Minimally Effective in db/db or ob/ob Mice
Eight-week-old male db/db (A–F) or ob/ob mice (G–K) were subjected to a three-week treatment of vehicle or Celastrol (100 μg/kg) (daily, i.p.). (A) Body weight (g) and (B) percent decrease in bodyweight of db/db mice during the treatment (n=5 for each group). (C) three-day average of food intakes of db/db mice during the first week of treatment. Experiments were repeated in three independent cohorts. (D) Lean mass (g) and (E) fat percentage (%) of db/db mice determined by DEXA scans after three weeks treatment (n=5 for each group). DEXA scans were done on two different cohorts. (F) Plasma leptin levels before, 12 and 24 days after Celastrol treatment (n=5 for each group). (G) Body weight (g) and (H) percent decrease in bodyweight of ob/ob mice during the treatment (n=8 for vehicle and n=10 for Celastrol group). (I) Three-day average of food intakes of ob/ob mice during the second week of the treatment. (J) Lean mass (g) and (K) fat percentage (%) on three weeks of treatment (n=6 for vehicle and n=5 for Celastrol group) measured by DEXA scan. DEXA scans were performed in two different cohorts. Error bars are represented as mean ± SEM. p values were determined by Student’s t test. See also Figure S2 and S7.
Figure 4
Figure 4. Oral Administration of Celastrol Reduces Body Weight and Food Intake of DIO Mice
(A–C) DIO mice, (D–F) lean mice, (G–I) db/db or (J–L) ob/ob mice were subjected to oral administration of vehicle (captisol) or Celastrol (10 mg/kg) for three weeks. (A) Body weight (g) and (B) percent decrease (%) in body weight of DIO mice during the treatment. (C) The average of three-day food intakes of DIO mice during the first week of treatment. (n=5 for vehicle group and n=4 for Celastrol group in (A–C)). Experiments on DIO mice were independently repeated twice. (D) Body weight (g) and (E) percent decrease in body weight of lean mice during Celastrol treatment. (F) The averages of three-day food intakes (g) of the lean mice during the first week of treatment. N=5 for each group in (D–F). (G) Body weight (g) and (H) percent decrease in body weight of db/db mice during the treatment. (I) The average of three-day food intake of db/db mice during the first week of treatment. (n=4 for vehicle and n=5 for Celastrol treatment in (G–I). (J) Body weight (g) and (K) percent decrease in body weight of ob/ob mice during Celastrol treatment. (L) The average of three-day food intake (g) of ob/ob mice during the first week of treatment (N=5 for each group in (J–L)). Error bars are represented as mean ± SEM. p values were determined by two-way ANOVA (A and B) or Student’s t test (*p < 0.05, **p < 0.01, ***p < 0.001).
Figure 5
Figure 5. Celastrol Acts as a Leptin Sensitizer
(A and B) Vehicle or Celastrol (150 μg/kg) were administered to lean mice for two days and each group was subsequently received either saline (n=9 for vehicle and n=11 for Celastrol subgroup) or leptin (n=12 for each subgroup) (5 mg/kg). (A) Food intake and (B) body weight change during 24-hour period following saline/leptin injections. Experiments were repeated in two independent cohorts. (C and D) Vehicle (n=12) or Celastrol (n=10; 150 μg/kg) were administered to DIO mice for two days and each group of mice was received either saline (n=6 vehicle; n=5 Celastrol) or leptin (n=6 vehicle; n=5 Celastrol) (1 mg/kg). (C) Food intake (g) and (D) body weight change (g) during 16-hour period following saline/leptin injections. These experiments were independently repeated two times. (E and F) ob/ob mice were treated with either vehicle (n=9) or Celastrol (100 μg/kg, n=9) for the next five days. For the next one week, each group of mice was also treated with either saline or leptin (0.1 mg/kg) (n=5 saline and n=4 leptin). (E) Percent decrease in body weight. (F) Percent suppression of food intake during leptin treatment. Experiments were repeated in two independent cohorts. Error bars are represented as mean ± SEM. p values were determined by Student’s t test (*p < 0.05, **p < 0.01, ***p < 0.001).
Figure 6
Figure 6. Celastrol Potentiates Leptin Signaling and Reduces ER Stress
(A and B) Vehicle or Celastrol (500 μg/kg) were administered to DIO. 15 hours later, each group of mice was treated with either saline or leptin (1 mg/kg) for 40 minutes. (A) Immunoblot analysis of Stat3Tyr705 phosphorylation, total Stat3, and actin protein levels from the hypothalamus (B) Ratio of signal intensities of pStatTyr705 to total Stat3. (C–F) DIO mice were treated with Celastrol (100 μg/kg) or vehicle by i.p. injection daily for four days. (C) Pomc, (D) Agrp, (E) Npy and (F) Socs3 mRNA expression in the hypothalamus. (G–I) DIO mice were administered with Celastrol (100 μg/kg) or vehicle (i.p., daily) for three days. On the fourth day, 100 or 250 μg/kg of Celastrol or vehicle was administered six hours before the hypothalamus was collected. (G) The quantified ratio of the signals of phosphorylated PERK (Thr980) to total PERK of the hypothalamus samples from four independent experiments in Figure S3A–H. (H) SERCA2b and tubulin protein levels and (I) quantified signal intensity of SERCA2b to tubulin. Results in (G–I) were independently reproduced in four different cohorts. Error bars are represented as mean ± SEM. p values were determined by Student’s t test (*p < 0.05, **p < 0.01, ***p < 0.001). See also Figure S3 and S4.
Figure 7
Figure 7. Effect of Celastrol on Metabolic Measures
(A–C) DIO mice, (D–E) lean, (G–I) ob/ob or (J–L) db/db mice were placed into metabolic cages and received Celastrol (100 μg/kg) or vehicle once a day for three days. (A, D, G, J) Energy expenditure, (B, E, H, K) respiratory exchange ratios (RER; VCO2/VO2), and (C, F, I, L) ambulatory count (physical activity) from each group of mice are shown. Bar graphs represent average of two dark (24–36h and 48–60h) and two light cycles (12–24h and 36–48h). Data represented in Figure 7A–C are average of three independent cohorts. (For DIO mice, n=16 for vehicle and n=13 for Celastrol). For data and analysis for Figure 7A–C, see Supplemental Data S1. Data represented in Figure 7D–F are average of two independent cohorts (n=8 for vehicle and Celastrol). For ob/ob mice, n=4 for vehicle and Celastrol; for db/db mice, n=4 for vehicle and Celastrol). Error bars are represented as mean ± SEM. p values were determined by Student’s t test (*p < 0.05, **p < 0.01, ***p < 0.001). See also Figure S5 and S6.
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