Chemotherapy can induce weight normalization of morbidly obese mice despite undiminished ingestion of high fat diet

Abstract

Morbidly obese patients who accomplish substantial weight loss often display a long-term decline in their resting metabolism, causing even relatively restrained caloric intake to trigger a relapse to the obese state. Paradoxically, we observed that morbidly obese mice receiving chemotherapy for cancer experienced spontaneous weight reduction despite unabated ingestion of their high fat diet (HFD). This response to chemotherapy could also be achieved in morbidly obese mice without cancer. Optimally dosed methotrexate (MTX) or cyclophosphamide (CY) enabled the mice to completely and safely normalize their body weight despite continued consumption of obesogenic quantities of HFD. Weight reduction was not attributable to decreased HFD intake, enhanced energy expenditure or malabsorption. MTX or CY dosing significantly depleted both adipose tissue and preadipocyte progenitors. Remarkably, however, despite continued high fat feeding, a compensatory increase in hepatocyte lipid storage was not observed, but rather the opposite. Gene microarray liver analyses demonstrated that HFD mice receiving MTX or CY experienced significantly inhibited lipogenesis and lipid storage, whereas Enho (energy homeostasis) gene expression was significantly upregulated. Further metabolic studies employing a human hepatocellular line revealed that MTX treatment preserved robust oxidative phosphorylation, but also promoted mitochondrial uncoupling with a surge in proton leak. This is the first report that certain optimally dosed chemotherapeutic agents can induce weight loss in morbidly obese mice without reduced dietary intake, apparently by depleting stores of adipocytes and their progenitors, curtailment of lipogenesis, and inconspicuous disposal of incoming dietary lipid via a steady state partial uncoupling of mitochondrial oxidative phosphorylation.

Cyclophosphamide-induced male subfertility in mice: An assessment of the potential benefits of Maca supplement

“…In the groups where Maca at 500 mg/kg (Figures 5e and 6e) and 1,000 mg/ kg (Figures 5f and 6f) alone were administered, the histology of the testis was normal and well preserved, with features characteristic of tubules at the later phase of stage of XII; showing a row of mature primary spermatocytes and elongated spermatids with fewer intermediate germ cells (round spermatid) observed, and numerous elongated spermatids whose tails radiate into the tubular lumen. Table 3 shows In this study, administration of cyclophosphamide was associated with significant weight loss, which is consistent with reports of previous studies in rodents (Kanno, Sensiate, Aparecida de Paula, & Salles, 2009;Kumar, Singh, & Reddy, 2013;Latha & Panikkar, 1999;Myers et al, 2017). Weight loss is a common side-effect of cyclophosphamide therapy.…”

“…Figures 3c and 4c), there was minimal swelling and cellular debris; and the duct epithelium and cells were better preserved, compared to the cyclophosphamide-only group. There was also loss of interstitial space between In this study, administration of cyclophosphamide was associated with significant weight loss, which is consistent with reports of previous studies in rodents (Kanno, Sensiate, Aparecida de Paula, & Salles, 2009;Kumar, Singh, & Reddy, 2013;Latha & Panikkar, 1999;Myers et al, 2017). In the group where Maca alone was administered at 500 mg/kg (Figures 3e and 4e), there was an increase in sperm concentration within the ducts; duct epithelium and cells were normal and well preserved.…”

“…Weight loss is a common side-effect of cyclophosphamide therapy. Mechanisms responsible for this would include a direct effect upon energy metabolism, and more recently, there are suggestions of the antiproliferative effects of cyclophosphamide on adipocyte progenitors (Myers et al, 2017). However, administration of CYP-treated mice; this is in contrast to the results of a number of studies that have reported that Maca administration did not have significant effects on body weight (Bilal et al, 2016;Chung, Rubio, Gonzales, Gasco, & Gonzales, 2005;Guo et al, 2016;Ruiz-Luna et al, 2005), or that it lowered body mass index (Gonzales, 2012).…”

Evaluation of Nutritional Status of Colorectal Cancer Patients from Algerian East Using Anthropometric Measurements and Laboratory Assessment

“…BMI class change from normal to underweight was higher for gastrointestinal than other malignancies ( 24 ; 27 ). In a recent report, certain chemotherapeutic agents may cause weight loss in obese mice by depleting stores of adipocytes ( 28 ).…”

Methotrexate attenuates vascular inflammation through an adenosine-microRNA-dependent pathway

“…Previous reports suggested that MTX can ameliorate diet-induced insulin resistance and inflammation ( DeOliveira et al, 2012 ; Myers et al, 2017 ), although the mechanisms remained poorly understood. To evaluate the effective dose of MTX on Mir181b expression in vivo, C57Bl6 mice were injected with 0.5 mg/kg or 1.0 mg/kg of MTX.…”