Obesity-induced blood-brain-barrier dysfunction during postnatal development

• Grant number: 23/05465-3
• Support Opportunities: Scholarships abroad - Research
• Effective date (Start): October 01, 2023
• Effective date (End): September 30, 2024
• Field of knowledge: Health Sciences - Nutrition - Malnutrition and Physiological Development
• Principal Investigator: Cristiano Mendes da Silva
• Grantee: Cristiano Mendes da Silva
• Host Investigator: Carol Fuzeti Elias
• Host Institution: Instituto de Saúde e Sociedade (ISS). Universidade Federal de São Paulo (UNIFESP). Campus Baixada Santista. Santos , SP, Brazil
• Research place: University of Michigan, United States

Abstract

Puberty is a developmental period of physiologic insulin resistance. Increase in insulin secretion stimulates adipose tissue accrual and typical adult fat distribution. Once established, insulin resistance also allows for increased glucose availability and growth. Leptin and leptin resistance are important players in this equation. Leptin, however, is not only a metabolic or "adipostat" hormone. It is also crucial for brain development. Circulating levels of leptin increase 5 to 10-fold at around 10 days of age in rodents independently of fat mass and decrease to adult levels at around 20 days of age. This postnatal leptin surge is associated with synaptic plasticity, myelination, and neurite outgrowth. In a recent publication, Dr. Elias laboratory analyzed changes in hypothalamic transcripts expression in wild type and obese (Lepob) mice during pubertal transition. Through independent and overlapping analyses of three RNAseq database, they identified genes associated with leptin signaling and early postnatal development. Differentially expressed genes were highly enriched in the extracellular matrix and vasculature. Due to the relevance of blood brain barrier (BBB) for metabolism, Dr. Elias laboratory hypothesize that postnatal leptin surge has a role in hypothalamic vasculogenesis and the establishment of the BBB, both key for the postnatal development of the hypothalamic neuroendocrine function. So in this pilot study, we will use in vivo and in vitro approaches to assess the postnatal development of hypothalamic BBB in nutritional obese (small litter size) and Lepob mice. We will also assess if the postnatal leptin surge is sufficient for the typical development of hypothalamic BBB and energy balance. (AU)