Estradiol protects proopiomelanocortin neurons against insulin resistance

Jian Qiu, Martha A. Bosch, Cecilia Meza, Uyen Vy Navarro, Casey C. Nestor, Edward J. Wagner, Oline Ronnekleiv, Martin Kelly

Research output: Contribution to journalArticle

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Abstract

Insulin resistance is at the core of the metabolic syndrome, and men exhibit a higher incidence of metabolic syndrome than women in early adult life, but this sex advantage diminishes sharply when women reach the postmenopausal state. Because 17β-estradiol (E2) augments the excitability of the anorexigenic proopiomelanocortin (POMC) neurons, we investigated the neuroprotective effects of E2 against insulin resistance in POMC neurons from diet-induced obese (DIO) female and male mice. The efficacy of insulin to activate canonical transient receptor potential 5 (TRPC5) channels and depolarize POMC neurons was significantly reduced in DIO male mice but not in DIO female mice. However, the insulin response in POMC neurons was abrogated in ovariectomized DIO females but restored with E2 replacement. E2 increased T-type calcium channel Cav3.1 messenger RNA (mRNA) expression and whole-cell currents but downregulated stromal-interaction molecule 1mRNA, which rendered POMC neurons more excitable and responsive to insulin-mediated TRPC5 channel activation. Moreover, E2 prevented the increase in suppressor of cytokine signaling-3 mRNA expression with DIO as seen in DIO males. As proof of principle, insulin [Intracerebroventricular injection into the third ventricle (ICV)] decreased food intake and increased metabolism in female but not male Guinea pigs fed a high-fat diet. The uncoupling of the insulin receptor from its downstream effector system was corroborated by the reduced expression of phosphorylated protein kinase B in the arcuate nucleus of male but not female Guinea pigs following insulin. Therefore, E2 protects female POMC neurons from insulin resistance by enhancing POMC neuronal excitability and the coupling of insulin receptor to TRPC5 channel activation.

Original languageEnglish (US)
Pages (from-to)647-664
Number of pages18
JournalEndocrinology
Volume159
Issue number2
DOIs
StatePublished - Feb 1 2018

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Pro-Opiomelanocortin
Insulin Resistance
Estradiol
Neurons
Diet
Insulin
Obese Mice
Insulin Receptor
Guinea Pigs
T-Type Calcium Channels
Proto-Oncogene Proteins c-akt
Messenger RNA
Arcuate Nucleus of Hypothalamus
Third Ventricle
High Fat Diet
Neuroprotective Agents
Down-Regulation
Eating
Cytokines
Injections

ASJC Scopus subject areas

  • Endocrinology

Cite this

Qiu, J., Bosch, M. A., Meza, C., Navarro, U. V., Nestor, C. C., Wagner, E. J., ... Kelly, M. (2018). Estradiol protects proopiomelanocortin neurons against insulin resistance. Endocrinology, 159(2), 647-664. https://doi.org/10.1210/en.2017-00793

Estradiol protects proopiomelanocortin neurons against insulin resistance. / Qiu, Jian; Bosch, Martha A.; Meza, Cecilia; Navarro, Uyen Vy; Nestor, Casey C.; Wagner, Edward J.; Ronnekleiv, Oline; Kelly, Martin.

In: Endocrinology, Vol. 159, No. 2, 01.02.2018, p. 647-664.

Research output: Contribution to journalArticle

Qiu J, Bosch MA, Meza C, Navarro UV, Nestor CC, Wagner EJ et al. Estradiol protects proopiomelanocortin neurons against insulin resistance. Endocrinology. 2018 Feb 1;159(2):647-664. https://doi.org/10.1210/en.2017-00793
Qiu, Jian ; Bosch, Martha A. ; Meza, Cecilia ; Navarro, Uyen Vy ; Nestor, Casey C. ; Wagner, Edward J. ; Ronnekleiv, Oline ; Kelly, Martin. / Estradiol protects proopiomelanocortin neurons against insulin resistance. In: Endocrinology. 2018 ; Vol. 159, No. 2. pp. 647-664.
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