Leptin resistance is not the primary cause of weight gain associated with reduced sex hormone levels in female mice

Regina P da Silva, Thais T Zampieri, João A B Pedroso, Vanessa S Nagaishi, Angela M Ramos-Lobo, Isadora C Furigo, Niels O Câmara, Renata Frazão, Jose Donato

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)


Several studies have shown that estrogens mimic leptin's effects on energy balance regulation. However, the findings regarding the consequences of reduced sex hormone levels on leptin sensitivity are divergent. In the present study, we employed different experimental paradigms to elucidate the interaction between estrogens, leptin, and energy balance regulation. We confirmed previous reports showing that ovariectomy caused a reduction in locomotor activity and energy expenditure leading mice to obesity and glucose intolerance. However, the acute and chronic anorexigenic effects of leptin were preserved in ovariectomized (OVX) mice despite their increased serum leptin levels. We studied hypothalamic gene expression at different time points after ovariectomy and observed that changes in the expression of genes involved in leptin resistance (suppressors of cytokine signaling and protein-tyrosine phosphatases) did not precede the early onset of obesity in OVX mice. On the contrary, reduced sex hormone levels caused an up-regulation of the long form of the leptin receptor (LepR), resulting in increased activation of leptin signaling pathways in OVX leptin-treated animals. The up-regulation of the LepR was observed in long-term OVX mice (30 d or 24 wk after ovariectomy) but not 7 days after the surgery. In addition, we observed a progressive decrease in the coexpression of LepR and estrogen receptor-α in the hypothalamus after the ovariectomy, resulting in a low percentage of dual-labeled cells in OVX mice. Taken together, our findings suggest that the weight gain caused by reduced sex hormone levels is not primarily caused by induction of a leptin-resistance state.

Original languageEnglish
Pages (from-to)4226-4236
Number of pages11
Issue number11
Early online date21 Aug 2014
Publication statusPublished - 1 Nov 2014
Externally publishedYes


São Paulo Research Foundation
(São Paulo Research Foundation, FAPESP-Brazil) Grants 2010/
18086 – 0 (to J.D.), 2012/12202– 4 (to R.F.), 2012/02270 –2
(to N.O.C.), 2012/15517– 6 (to T.T.Z.), 2013/00801–3 (to
R.P.d.S.), 2013/16374 –7 (to V.S.N.), and 2013/21722– 4 (to
I.C.F.) and by the International Brain Research Organization
(Return Home Fellowship) (J.D.)


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