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

in Journal of Endocrinology
Authors:
Hui Yu Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA

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Zoe Thompson Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA

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Sylee Kiran Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA
School of Literature, Science, and Arts, University of Michigan, Ann Arbor, Michigan, USA

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Graham L Jones Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA
Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, USA

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Lakshmi Mundada Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA

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Surbhi Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA

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Marcelo Rubinstein Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas and Facultad de Ciencias Exactas y Naturales, Universidad de Buenos, Buenos Aires, Argentina

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Malcolm J Low Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA

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Correspondence should be addressed to M J Low: mjlow@umich.edu
DOI:
https://doi.org/10.1530/JOE-19-0576
Volume/Issue:
Volume 245: Issue 1
Article Type:
Research Article
Page Range:
115–127
Online Publication Date:
Apr 2020
Copyright:
© 2020 Society for Endocrinology 2020
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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.

Supplementary Materials

    • Supplementary Figure 1 Comparison of body composition between Pomc+/+ and Pomc&#x2206;1/&#x2206;1 dams during gestation. (A). Lean mass and (B) fat mass comparisons between Pomc+/+ and Pomc&#x2206;1/&#x2206;1 dams before pregnancy (NP), at late pregnancy (dpc17.5 and dpc18.5) and at ppd0 (n=6-10). (C). Changes in fat mass from stages NP to dpc18.5 (D) and from stages NP to ppd0. NP, non-pregnant; dpc, days post coitum; ppd, postpartum day. Two-way ANOVAs followed by Bonferroni&#x2019;s post-hoc multiple comparison tests for pair-wise comparisons of fat mass and lean mass. Unpaired Student&#x2019;s two-tailed t-tests were used to determine the significant differences between genotypes in changes of fat mass. Data shown are the mean &#x00B1; SEM. *P < 0.05.
    • Supplementary Figure 2 Increased circulating Leptin Re at dpc18.5. Two-way ANOVA followed by Bonferroni&#x2019;s post-hoc multiple comparison tests for pair-wise comparisons were performed to determine the genotype and stage effects (n=6-10). Data shown are the mean &#x00B1; SEM. *P < 0.05.
    • Supplementary Figure 3 Reduced Pomc transcript abundance in placenta relative to medial basal hypothalamus. An Unpaired Student&#x2019;s two-tailed t-test was used to determine the significance between the raw Ct values for qRT-PCR amplification of 100ng cDNA obtained from ARC or placenta tissue samples obtained from ppd18.5 wildtype mice (n=8-12). ****P< 0.001.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2020 Society for Endocrinology 2020
Page(s):
13
Article Type:
Research Article
Received Date:
29 Jan 2020
Accepted Date:
06 Feb 2020
Print Publication Date:
01 Apr 2020
Online Publication Date:
Apr 2020
Keywords:
Pomc; leptin; leptin receptor; pregnancy; enhancers