Camptothecin effectively treats obesity in mice through GDF15 induction

Abstract

Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight through activation of hindbrain receptor glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) in rodents and nonhuman primates, thus endogenous induction of this peptide holds promise for obesity treatment. Here, through in silico drug-screening methods, we found that small molecule Camptothecin (CPT), a previously identified drug with potential antitumor activity, is a GDF15 inducer. Oral CPT administration increases circulating GDF15 levels in diet-induced obese (DIO) mice and genetic ob/ob mice, with elevated Gdf15 expression predominantly in the liver through activation of integrated stress response. In line with GDF15’s anorectic effect, CPT suppresses food intake, thereby reducing body weight, blood glucose, and hepatic fat content in obese mice. Conversely, CPT loses these beneficial effects when Gdf15 is inhibited by a neutralizing antibody or AAV8-mediated liver-specific knockdown. Similarly, CPT failed to reduce food intake and body weight in GDF15’s specific receptor GFRAL-deficient mice despite high levels of GDF15. Together, these results indicate that CPT is a promising anti-obesity agent through activation of GDF15-GFRAL pathway.

Research Progress on the Role and Mechanism of GDF15 in Body Weight Regulation

“…Zhang et al [54] conducted an aerobic exercise intervention on 24 sedentary patients with severe obesity and found that plasma GDF15 increased after the intervention, and the amount of change in GDF15 was correlated with the reduction in total fat mass. Transgenic mice expressing human GDF15 or oral camptothecin-induced mouse GDF15 expression showed similar results [52], possibly due to increased expression of lipolytic genes in adipose tissue to prevent HFD-induced obesity. Zhang et al [6] found that in mice with high levels of GDF15 in the liver, the expression of genes related to fatty acid β-oxidation and ketosis, such as Ppara, Pgc1a, Cpt1a, Acox, Cpt1a, and Hmgcs2, was dramatically upregulated.…”

“…Mice overexpressing GDF15 exhibit improved glucose tolerance and insulin sensitivity and reduced insulin levels and insulin resistance [59], which disappear after GDF15 knockout [25, 60]. Lu et al [52] also induced the expression of GDF15 by camptothecin to increase glucose tolerance. Neutralizing GDF15 with an antibody abolished this effect, suggesting that GDF15 can improve insulin sensitivity and reverse insulin resistance.…”

“…Neutralizing GDF15 with an antibody abolished this effect, suggesting that GDF15 can improve insulin sensitivity and reverse insulin resistance. GDF15 depletion does not cause significant changes in In NCD-fed mice [19,26,44] In HFD-fed mice [27,29,47,51] In HFD-fed mice [41,51,52] In NCD-fed mice [19,26,44] In HFD-fed mice [45][46][47][48] In obese cynomolgus monkeys [40,49] In HFD-fed mice [45][46][47] In obese mouse models [24,49] In obese mouse models [24,49] In obese cynomolgus monkeys [40,49] In obese cynomolgus monkeys [40,49] In shrews [50] In shrews [50] External factors (drugs/ surgery/exercise)…”

Astaxanthin Supplemented with High-Intensity Functional Training Decreases Adipokines Levels and Cardiovascular Risk Factors in Men with Obesity

“…Treatments to reduce obesity and its related health problems remain elusive. Pharmacological and surgical approaches in obese patients are associated with side effects and have variable effectiveness [ 17 , 18 ]. Reducing energy consumption, increasing energy expenditure, and increasing muscle mass hold promise in the management of obesity and associated complications [ 19 , 20 ].…”

The Emerging Role of Cyclin-Dependent Kinase Inhibitors in Treating Diet-Induced Obesity: New Opportunities for Breast and Ovarian Cancers?

“…Furthermore, the potential combination of nutraceuticals and/or dietary supplements with CDKi could open a new research pathway to be further exploited in the cancer research field. As a matter of fact, a recently published work has also shown Camptothecin—an anticancer-proved molecule targeting topoisomerase enzymes—to be effective in treating DIO in vivo, probably throughout the activation of the growth differentiation factor GDF15, therefore decreasing BMI, blood glucose, and hepatic fatness [ 197 ]. This newfound article represents another example of the increasing interest that antitumor agents may have in the management of obesity, linking cancer mechanisms with those underlying DIO development, which undoubtedly need further investigation and CTs set up to effectively understand their efficacy and safety of use.…”