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PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction
David Garcia-Galiano, … , Jennifer W. Hill, Carol F. Elias
David Garcia-Galiano, … , Jennifer W. Hill, Carol F. Elias
Published December 7, 2017
Citation Information: JCI Insight. 2017;2(23):e96728. https://doi.org/10.1172/jci.insight.96728.
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Research Article Reproductive biology

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

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Abstract

The role of PI3K in leptin physiology has been difficult to determine due to its actions downstream of several metabolic cues, including insulin. Here, we used a series of mouse models to dissociate the roles of specific PI3K catalytic subunits and of insulin receptor (InsR) downstream of leptin signaling. We show that disruption of p110α and p110β subunits in leptin receptor cells (LRΔα+β) produces a lean phenotype associated with increased energy expenditure, locomotor activity, and thermogenesis. LRΔα+β mice have deficient growth and delayed puberty. Single subunit deletion (i.e., p110α in LRΔα) resulted in similarly increased energy expenditure, deficient growth, and pubertal development, but LRΔα mice have normal locomotor activity and thermogenesis. Blunted PI3K in leptin receptor (LR) cells enhanced leptin sensitivity in metabolic regulation due to increased basal hypothalamic pAKT, leptin-induced pSTAT3, and decreased PTEN levels. However, these mice are unresponsive to leptin’s effects on growth and puberty. We further assessed if these phenotypes were associated with disruption of insulin signaling. LRΔInsR mice have no metabolic or growth deficit and show only mild delay in pubertal completion. Our findings demonstrate that PI3K in LR cells plays an essential role in energy expenditure, growth, and reproduction. These actions are independent from insulin signaling.

Authors

David Garcia-Galiano, Beatriz C. Borges, Jose Donato Jr., Susan J. Allen, Nicole Bellefontaine, Mengjie Wang, Jean J. Zhao, Kenneth M. Kozloff, Jennifer W. Hill, Carol F. Elias

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Figure 1

Deletion of PI3Kα and PI3Kβ in LR cells causes changes in energy expenditure, growth, and puberty.

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Deletion of PI3Kα and PI3Kβ in LR cells causes changes in energy expendi...
(A) Reduced body weight in male (M) LRΔα+β (n = 13) versus αfl+βfl [n = 21; F(1,32) = 19.67, P < 0.0001] mice and in female (F) LRΔα+β (n = 13) versus αfl+βfl [n = 16; F(1,27) = 28.37, P < 0.0001] mice from 2 independent cohorts. (B) Reduced body composition in LRΔα+β mice (n = 8/group, males; t14 = 5.83, P < 0.0001 for lean mass; t14 = 2.81, P = 0.014 for fat mass). (C) Reduced body length at 9 weeks of age, in male LRΔα+β (n = 8) versus αfl+βfl (n = 11; t17 = 5.28, P < 0.0001) mice and in female LRΔα+β (n = 10) versus αfl+βfl (n = 18; t17 = 5.28, P = 0.002) mice. (D–F) CLAMS study (n = 8/group, males) detected differences in (D) 24-hour food intake normalized to body weight (t14 = 5.83, P < 0.0001), (E) in 4-day energy expenditure, and (F) averages for dark and light phases in LRΔα+β versus αfl+βfl mice (t14 = 2.56, P = 0.024 for dark phase; t14=3.19, P = 0.006 for light phase). (G) Increased BAT Ucp1 mRNA in adult male LRΔα+β (n = 6) versus αfl+βfl (n = 5; t9 = 2.41, P = 0.04) mice. (H) Increased locomotor activity (4 days, n = 8/group) and (I) averages for dark and light phases in male LRΔα+β (t14 = 2.6, P = 0.021 for dark phase; t14=3.42, P = 0.004 for light phase) mice. (J) Glucose and (K) insulin levels in oral glucose tolerance test (OGTT; t12 = 2.62, P = 0.02 at basal levels compared with αfl+βfl), or circulating glucose in insulin tolerance test (ITT, L) at basal (0 minutes), 15, 30, 60, and 120 minutes after oral glucose (n = 7/group, males). (M) Delayed vaginal opening in LRΔα+β (n = 12) versus αfl+βfl (n = 16; t26 = 2.51, P = 0.019) mice and (N) first estrus in LRΔα+β (n = 13) versus αfl+βfl (n = 12) mice. (O) Normal estrous cycle length in LRΔα+β (n = 16) versus αfl+βfl (n = 17; t31 = 1.81, P = 0.08) mice. Circles in bar graphs represent individual mice. Values are presented as mean ± SEM. *P < 0.05, **P < 0.01, by repeated-measures 2-way ANOVA with Holm-Sidak’s multiple comparisons (A) and by 2-tailed Student’s t test (B–O). LRΔα+β, deletion of PI3Kα and PI3Kβ in LR cells.

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