Leptin receptor signaling supports cancer cell metabolism through suppression of mitochondrial respiration in vivo.
Obesity represents a risk factor for certain types of cancer. Leptin, a hormone predominantly produced by adipocytes, is elevated in the obese state. In the context of breast cancer, leptin derived from local adipocytes is present at high concentrations within the mammary gland. A direct physiological role of peripheral leptin action in the tumor microenvironment in vivo has not yet been examined. Here, we report that mice deficient in the peripheral leptin receptor, while harboring an intact central leptin signaling pathway, develop a fully mature ductal epithelium, a phenomenon not observed in db/db mice to date. In the context of the MMTV-PyMT mammary tumor model, the lack of peripheral leptin receptors attenuated tumor progression and metastasis through a reduction of the ERK1/2 and Jak2/STAT3 pathways. These are tumor cell-autonomous properties, independent of the metabolic state of the host. In the absence of leptin receptor signaling, the metabolic phenotype is less reliant on aerobic glycolysis and displays an enhanced capacity for β-oxidation, in contrast to nontransformed cells. Leptin receptor-free tumor cells display reduced STAT3 tyrosine phosphorylation on residue Y705 but have increased serine phosphorylation on residue S727, consistent with preserved mitochondrial function in the absence of the leptin receptor. Therefore, local leptin action within the mammary gland is a critical mediator, linking obesity and dysfunctional adipose tissue with aggressive tumor growth.
Touchstone Diabetes Center, Dallas, TX, USA.
Jiyoung
J
Park
Christine M
CM
Kusminski
Streamson C
SC
Chua
Philipp E
PE
Scherer
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured
D020738:Leptin; D054411:Receptors, Leptin