Oncotarget

Research Papers:

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

Cheryl E. Myers _, Dominique B. Hoelzinger, Tiffany N. Truong, Lindsey A. Chew, Arpita Myles, Leena Chaudhuri, Jan B. Egan, Jun Liu, Sandra J. Gendler, Peter A. Cohen

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Abstract

Cheryl E. Myers1, Dominique B. Hoelzinger1, Tiffany N. Truong1, Lindsey A. Chew1, Arpita Myles2, Leena Chaudhuri2, Jan B. Egan3, Jun Liu1, Sandra J. Gendler1,2,4, Peter A. Cohen2,4

1Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA

2Department of Immunology, Mayo Clinic, Scottsdale, AZ, USA

3Center for Individualized Medicine, Mayo Clinic, Scottsdale, AZ, USA

4Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA

Correspondence to:

Cheryl E. Myers, email: myers.cheryl@mayo.edu

Peter A. Cohen, email: cohen.peter@mayo.edu

Keywords: obesity, chemotherapy, proton leak, preadipocyte, lipogenesis

Received: July 27, 2016    Accepted: December 05, 2016    Published: January 10, 2017

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.

Author Information

Cheryl E. Myers
Primary Contact  _

Dominique B. Hoelzinger

Tiffany N. Truong

Lindsey A. Chew

Arpita Myles

Leena Chaudhuri

Jan B. Egan

Jun Liu

Sandra J. Gendler

Peter A. Cohen


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