The postnatal leptin surge in the establishment of the hypothalamus-adipose axis

• Applicant: Dr. Elena Schmidt
• Subject Area: Developmental Biology ; General Genetics and Functional Genome Biology
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 442385375

Obesity and its associated diseases such as type 2 diabetes mellitus and cardiovascular disease constitute serious global health concerns. For the prevention of obesity and its metabolic sequelae it is important to understand the processes that lead to the abnormal or excessive fat accumulation of adipose tissue. To ensure a stable adipose tissue mass in the body, organs such as the adipose tissue and the brain, are in constant communication with each other. Leptin is an adipose tissue-derived hormone which decreases appetite and increases energy expenditure by functioning as the afferent component of a negative feedback loop. One way in which leptin achieves this is by activating adipose afferent fibers from the periphery, such as the adipose tissue, that signal to the central nervous system. The central nervous system integrates the received information and disseminates the signal via sympathetic outflow to the adipose tissue. Disruption of this critical hypothalamus-adipose axis results in hyperphagia, positive energy balance, and ultimately obesity. The neuronal network regulating food intake is established early in development. In newborn mice, an up to 10-fold increase in both leptin plasma and leptin mRNA in the dorsal white adipose tissue can be observed from postnatal day (P) 4 onwards, peaking at P10 and reaching normal levels again by P16. Although leptin´s physiological functions have been extensively studied, the purpose of this postnatal ‘leptin surge’ and its role in the establishment of the afferent feedback loop that regulates leptin gene expression is not known. Here I present an ambitious research proposal aimed at unravelling the linkage between the postnatal leptin surge and white adipose tissue innervation in the development of the hypothalamus-adipose axis and identifying enhancer elements that govern leptin gene expression during this process. This approach involves modern mouse transgenics in concert with state-of-the-art imaging and functional genomics techniques aiming at i. characterizing white adipose tissue innervation during the postnatal leptin surge in wild type and leptin-deficient (ob/ob) animals using the Adipo-Clear technique; and ii) by performing H3K27ac HiChIP in white adipocytes a) deciphering the gene regulatory mechanisms of leptin expression during the postnatal leptin surge, and b) identifying novel sequences that show similar trends of enhancer activation as leptin during the postnatal leptin surge. Collectively, this multi-sided, collaborative research project aims to provide insights into key mechanisms that establish proper regulation of leptin gene expression in adipose tissue and will have important implications for understanding the basis of leptin-dependent appetite regulation, as well as obesity.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Matthew Stephen Rodeheffer, Ph.D.