Early pharmacological inhibition of angiotensin-I converting enzyme activity induces obesity in adulthood.

Kely De Picoli Souza,Sylvia M A Silva,Elton D Da Silva,Jaqueline Luz,Charlles H M Castro,Felipe C G Reis,Joã£O B Pesquero,Jorge L Pesquero,Edson L Dos Santos,Elice C Batista

doi:10.3389/fphar.2015.00075

Abstract

We have investigated early programming of body mass in order to understand the multifactorial etiology of obesity. Considering that the renin-angiotensin system (RAS) is expressed and functional in the white adipose tissue (WAT) and modulates its development, we reasoned whether early transitory inhibition of angiotensin-I converting enzyme activity after birth could modify late body mass development. Therefore, newborn Wistar rats were treated with enalapril (10 mg/kg of body mass) or saline, starting at the first day of life until the age of 16 days. Between days ninetieth and hundred and eightieth, a group of these animals received high fat diet (HFD). Molecular, biochemical, histological, and physiological data were collected. Enalapril treated animals presented hyperphagia, overweight, and increased serum level of triglycerides, total cholesterol and leptin, in adult life. Body composition analyses revealed higher fat mass with increased adipocyte size in these animals. Molecular analyses revealed that enalapril treatment increases neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) gene expression in hypothalamus, fatty acid synthase (FAS), and hormone-sensitive lipase (HSL) gene expression in retroperitoneal WAT, and decreases peroxixome proliferators-activated receptor (PPAR)γ, PPARα, uncoupling protein (UCP)2, and UCP3 gene expression in WAT. The results of the current study indicate that enalapril administration during early postnatal development increases body mass, adiposity and serum lipids in adulthood associated with enhanced food intake and decreased metabolic activity in WAT, predisposing to obesity in adulthood.

Highlights

Epidemiological studies have revealed associations between critical events in the early phases of development, such as pregnancy and suckling, and metabolic, cardiovascular diseases in the adult life (Langley-Evans, 2006, 2015)
Impact of high fat diet (HFD) in the Body Weight of Rats Treated with Enalapril To analyze the sensitivity of the iACE treated animals to a hypercaloric regimen, as well as the evolution of the effects of enalapril postnatal treatment, on the ninetieth day the rats were subdivided in four groups and fed with control (CD) or high fat (HFD) diet for 3 months
We showed that early postnatal treatment with an angiotensin converting enzyme (ACE) inhibitor, enalapril, applied to newborn rats during the first 16 days after birth is responsible for a programming in metabolism, favoring hyperphagia and white adipose tissue (WAT) accumulation

Summary

Introduction

Epidemiological studies have revealed associations between critical events in the early phases of development, such as pregnancy and suckling, and metabolic, cardiovascular diseases in the adult life (Langley-Evans, 2006, 2015). Gorski et al (2006) demonstrated that postnatal factors can overcome both genetic predisposition and prenatal factors in determining the development of adiposity, insulin sensitivity, and the brain pathways that mediate these functions. These authors have shown that obesityprone pup cross-fostered to obesity-resistant dams remained obese but improved their insulin sensitivity in adult life (Gorski et al, 2006). Obesity-resistant pups cross-fostered to genetically obese dams showed a diet-induced increase in adiposity, reduced insulin sensitivity and associated changes in hypothalamic neuropeptide, insulin, and leptin receptors, which might have contributed to their metabolic defects (Gorski et al, 2006)

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Results

Conclusion