期刊
FASEB JOURNAL
卷 34, 期 3, 页码 3902-3914出版社
WILEY
DOI: 10.1096/fj.201902357R
关键词
AGRP; arcuate nucleus; leptin; NPY; STAT
资金
- National Institute of Diabetes and Digestive and Kidney Diseases' National Hormone and Pituitary Program [14, 568]
- Agencia Nacional de Promocion Cientifica y Tecnologica [PICT 1343-2015, PICT 526-2016]
- Fundacion Rene Baron
- Fundacion Williams
- Consejo Nacional de Investigaciones Cientificas y Tecnicas
- Fundacion Bunge & Born-Oster Fellowship
- Health Research Council [14/568]
- Maurice Wilkins Centre for Molecular Biodiscovery
To study the pathological effects of continuous hyperprolactinemia on food intake mechanisms we used female mice that lack dopamine D2 receptors in lactotropes (lacDrd2KO). These mice had lifelong hyperprolactinemia, increased food intake, and gradual development of obesity from 5 to 10 months of age. Ongoing endogenous prolactin signaling in lacDrd2KO mice was evidenced by increased basal phosphorylation of STAT5b in hypothalamic areas related to food intake, such as the arcuate (ARN), dorsomedial (DMN), and ventromedial nuclei. In the ARN of young lacDrd2KO mice there were higher Prlr mRNA levels and in obese 10-month-old lacDrd2KO mice increased expression of the orexigenic genes Neuropeptide Y (Npy) and Agouti-related peptide, compared to controls. Furthermore, Npy expression was increased in the DMN, probably contributing to increased food intake and decreased expression of Uncoupling protein-1 in brown adipose tissue, both events favoring weight gain. Leptin resistance in obese lacD2RKO mice was evidenced by its failure to lower food intake and a dampened response of STAT3 phosphorylation, specifically in the mediobasal hypothalamus. Our results suggest that pathological chronically high prolactin levels, as found in psychiatric treatments or patients with prolactinomas, may impact on specific hypothalamic nuclei altering gene expression, leptin response, and food intake.
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