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 D Liu, Sandra J Gendler, Peter A Cohen

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5426-5438
Number of pages13
JournalOncotarget
Volume8
Issue number3
DOIs
StatePublished - 2017

Fingerprint

Obese Mice
High Fat Diet
Methotrexate
Weight Loss
Eating
Cyclophosphamide
Weights and Measures
Drug Therapy
Lipogenesis
Oxidative Phosphorylation
Lipids
Microarray Analysis
Energy Intake
Adipocytes
Energy Metabolism
Protons
Adipose Tissue
Hepatocytes
Neoplasms
Homeostasis

Keywords

  • Chemotherapy
  • Lipogenesis
  • Obesity
  • Preadipocyte
  • Proton leak

ASJC Scopus subject areas

  • Oncology

Cite this

Chemotherapy can induce weight normalization of morbidly obese mice despite undiminished ingestion of high fat diet. / Myers, Cheryl E.; Hoelzinger, Dominique B.; Truong, Tiffany N.; Chew, Lindsey A.; Myles, Arpita; Chaudhuri, Leena; Egan, Jan B.; Liu, Jun D; Gendler, Sandra J; Cohen, Peter A.

In: Oncotarget, Vol. 8, No. 3, 2017, p. 5426-5438.

Research output: Contribution to journalArticle

Myers, Cheryl E. ; Hoelzinger, Dominique B. ; Truong, Tiffany N. ; Chew, Lindsey A. ; Myles, Arpita ; Chaudhuri, Leena ; Egan, Jan B. ; Liu, Jun D ; Gendler, Sandra J ; Cohen, Peter A. / Chemotherapy can induce weight normalization of morbidly obese mice despite undiminished ingestion of high fat diet. In: Oncotarget. 2017 ; Vol. 8, No. 3. pp. 5426-5438.
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