Expression of a hypomorphic Pomc allele alters leptin dynamics during late pregnancy

Abstract

Proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC) are essential for normal energy homeostasis. Maximal ARC Pomc transcription is dependent on neuronal Pomc enhancer 1 (nPE1), located 12 kb upstream from the promoter. Selective deletion of nPE1 in mice decreases ARC Pomc expression by 70%, sufficient to induce mild obesity. Because nPE1 is located exclusively in the genomes of placental mammals, we questioned whether its hypomorphic mutation would also alter placental Pomc expression and the metabolic adaptations associated with pregnancy and lactation. We assessed placental development, pup growth, circulating leptin and expression of Pomc, Agrp and alternatively spliced leptin receptor (LepR) isoforms in the ARC and placenta of Pomc∆1/∆1 and Pomc+/+ dams. Despite indistinguishable body weights, lean mass, food intake, placental histology and Pomc expression and overall pregnancy outcomes between the genotypes, Pomc ∆1/∆1 females had increased pre-pregnancy fat mass that paradoxically decreased to control levels by parturition. However, Pomc∆1/∆1 dams had exaggerated increases in circulating leptin, up to twice of that of the typically elevated levels in Pomc+/+ mice at the end of pregnancy, despite their equivalent fat mass. Pomc∆1/∆1dams also had increased placental expression of soluble leptin receptor (LepRe), although the protein levels of LEPRE in circulation were the same as Pomc+/+ controls. Together, these data suggest that the hypomorphic Pomc∆1/∆1 allele is responsible for the perinatal super hyperleptinemia of Pomc∆1/∆1 dams, possibly due to upregulated leptin secretion from individual adipocytes.

Decreased sensitivity to the anorectic effects of leptin in mice that lack a Pomc-specific neural enhancer

“…Thus, the sensitized behavioral response to acute leptin treatment in our nPE1 KO mice may be due to MSH-independent mechanisms as the mice used in the current experiment presumably had decreased α-MSH levels during the time of testing. We replicated our previous findings indicating an overall decrease in Pomc mRNA in our nPE1 KO mice [25,30] as well as a slight decrease in Pomc mRNA in our nPE2 KO mice as compared to WT littermates (Figs 2A and 3A).…”

miR-519d downregulates LEP expression to inhibit preeclampsia development

“…Previous work also attests that, in comparison with pregnant women with normal BMI, PE patients showed higher levels of LEP and proinflammatory cytokines in plasma [ 25 ]. Moreover, upregulated LEP secretion can induce perinatal hyperleptinemia, which is one of the characteristics of PE [ 26 , 27 ]. Consistent with our study, it has been reported previously that LEP treatment could regulate placental trophoblast cells by affecting the cellular proliferation, invasion, and nutrient transport [ 28 ].…”