Deletion of miRNA processing enzyme Dicer in POMC-expressing cells leads to pituitary dysfunction, neurodegeneration and development of obesity

Abstract

MicroRNAs (miRNAs) have recently emerged as key regulators of metabolism. However, their potential role in the central regulation of whole-body energy homeostasis is still unknown. In this study we show that the expression of Dicer, an essential endoribonuclease for miRNA maturation, is modulated by nutrient availability and excess in the hypothalamus. Conditional deletion of Dicer in POMC-expressing cells resulted in obesity, characterized by hyperphagia, increased adiposity, hyperleptinemia, defective glucose metabolism and alterations in the pituitary-adrenal axis. The development of the obese phenotype was paralleled by a POMC neuron degenerative process that started around 3 weeks of age. Hypothalamic transcriptomic analysis in presymptomatic POMCDicerKO mice revealed the downregulation of genes implicated in biological pathways associated with classical neurodegenerative disorders, such as MAPK signaling, ubiquitin-proteosome system, autophagy and ribosome biosynthesis. Collectively, our results highlight a key role for miRNAs in POMC neuron survival and the consequent development of neurodegenerative obesity.

MicroRNA 375 Mediates the Signaling Pathway of Corticotropin-releasing Factor (CRF) Regulating Pro-opiomelanocortin (POMC) Expression by Targeting Mitogen-activated Protein Kinase 8

“…However, it has been reported that the dicer deletion using Pitx2-cre only has obvious effect on pituitary somatotropes (22), although Pitx2 is highly expressed in the Rathkes pouch at embryonic day 10.5 (44) and transiently expresses in the precursors of POMC-producing cells of the anterior gland and intermediate lobes (45). However, the dicer deletion using POMC-cre results in the disappearance of the intermediate lobe and reduction of the pituitary corticotropes (46); this suggests that microRNAs play important roles in regulating the proliferation and differentiation of POMC-positive cells. However, the expressing pattern and function of miR-375 in the developing pituitary gland should be elucidated in future studies.…”

MECHANISMS IN ENDOCRINOLOGY: Hypothalamic inflammation and nutrition

“…Interestingly, manipulation of autophagy in different subsets of neurons of the medium-basal hypothalamus produces different phenotypic outcomes. When autophagy is inhibited in AgRP neurons, mice eat less and are lean (64), whereas when autophagy is inhibited in POMC neurons, mice eat more and are obese (65,66). Thus, it seems that the regulation of autophagy in response to dietary stimuli is an important mechanism involved in the control of wholebody energy homeostasis.…”

Gonadotrope-specific Deletion of Dicer Results in Severely Suppressed Gonadotropins and Fertility Defects

“…These include mRNA expression, turnover, stability, and translational control (36 -41). Expression profiling studies have identified several miRNAs differentially regulated in whole pituitary (23,24), various pituitary cell lineages (42), human pituitary tumors (43)(44)(45), and in an immortalized gonadotrope cell line in response to GnRH treatment (46 -48). In addition, specific miRNAs regulating a repressor that selectively regulates LH levels in the female have also been identified (49).…”