title: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Myers
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Dominique B
authors.initials: DB
authors.lastname: Hoelzinger
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Tiffany N
authors.initials: TN
authors.lastname: Truong
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Chew
authors.affiliation: Department of Immunology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Arpita
authors.initials: A
authors.lastname: Myles
authors.affiliation: Department of Immunology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Leena
authors.initials: L
authors.lastname: Chaudhuri
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Egan
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA.|Department of Immunology, Mayo Clinic, Scottsdale, AZ, USA.|Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Gendler
authors.affiliation: Department of Immunology, Mayo Clinic, Scottsdale, AZ, USA.|Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cohen
mesh_terms: D017667:Adipocytes / Q000187:drug effects; D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology*; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism / Q000187:drug effects*; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009767:Obesity, Morbid; D011897:Random Allocation
chemical_list: D003520:Cyclophosphamide; D008727:Methotrexate
keywords: chemotherapy; lipogenesis; obesity; preadipocyte; proton leak