Modeling the impact of growth and leptin deficits on the neuronal regulation of blood pressure

Abstract

The risk of hypertension is increased by intrauterine growth restriction (IUGR) and preterm birth. In the search for modifiable etiologies for this life-threatening cardiovascular morbidity, a number of pathways have been investigated, including excessive glucocorticoid exposure, nutritional deficiency, and aberration in sex hormone levels. As a neurotrophic hormone intimately involved in cardiovascular regulation whose levels are influenced by glucocorticoids, nutritional status and sex hormones, leptin has emerged as a putative etiologic and thus therapeutic agent. As a product of maternal and late fetal adipocytes as well as the placenta, circulating leptin typically surges late in gestation and declines following delivery until the infant consumes sufficient leptin-containing breast milk or accrues sufficient leptin-secreting adipose tissue to reestablish circulating levels. The leptin deficiency seen in IUGR infants is a multifactorial manifestation of placental insufficiency, exaggerated glucocorticoid exposure and fetal adipose deficit. The preterm infant suffers from the same cascade of events, including separation from the placenta, antenatal steroid exposure and persistently underdeveloped adipose depots. Preterm infants remain leptin deficient beyond term gestation, rendering them susceptible to neurodevelopmental impairment and subsequent cardiovascular dysregulation. This pathologic pathway is efficiently modeled by placing neonatal mice into atypically large litters, thereby recapitulating the perinatal growth restriction-adult hypertension phenotype. In this model, neonatal leptin supplementation restores the physiologic leptin surge, attenuates leptin-triggered sympathetic activation in adulthood and prevents leptin- or stress-evoked hypertension. Further pathway interrogation and clinical translation are needed to fully test the therapeutic potential of perinatal leptin supplementation.

Renal injury in Seipin ‐deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: adipose tissue‐kidney crosstalk

“…Leptin deficiency increases the risk of hypertension (38). Blood pressure plays a pivotal role in renal damage, and it is slightly higher in CGL patients (39), whereas blood pressure was not changed in SKO mice (Table 1).…”

Origins of neonatal leptin deficiency in preterm infants

“…Less well known, but perhaps more important, is leptin’s role as a neurotrophic hormone during development(4, 5). Cord blood studies demonstrate that fetal leptin levels increase with advancing gestation(6, 7) and are dependent on both transplacental delivery and placental leptin production until around 32 weeks gestation(8). Only after 30-32 weeks, when the fetus starts to accrue significant amounts of adipose tissue, does the fetus become the main contributor to its own circulating leptin levels(8).…”

Integrated Analysis of Key Genes and Pathways Involved in Fetal Growth Restriction and Their Associations With the Dysregulation of the Maternal Immune System

“…LEP , the most highly significantly down-regulated gene in FGR placentas, encodes leptin, found in the circulation. Leptin plays a major role in the regulation of energy homeostasis and obesity and is involved in endocrine functions, including the regulation of immune and inflammatory responses, angiogenesis, reproduction, and bone formation ( Bodary et al, 2007 ; Steinbrekera and Roghair, 2016 ). Maternal and fetal leptin levels are correlated with FGR originating from damaged placental function ( Zareaan et al, 2017 ).…”