Journal Article

Doublecortin-like knockdown in mice attenuates obesity by stimulating energy expenditure in adipose tissue

Vreugdenhil, Erno, Scholten, Leonie, Boelen, Anita, Lalai, Reshma A., Kooijman, Sander, Pronk, Amanda C. M., Coomans, Claudia P., Hoogduin, Janna, Saaltink, Dirk-Jan, Kalsbeek, Andries, Rensen, Patrick C. N., Modder, Melanie, Tersteeg, Mayke M. H.

2024

Overview

Crosstalk between peripheral metabolic organs and the central nervous system is essential for body weight control. At the base of the hypothalamus, β-tanycytes surround the portal capillaries and function as gatekeepers to facilitate transfer of substances from the circulation into the cerebrospinal fluid and vice versa. Here, we investigated the role of the neuroplasticity gene doublecortin-like (DCL), highly expressed by β-tanycytes, in body weight control and whole-body energy metabolism. We demonstrated that DCL-knockdown through a doxycycline-inducible shRNA expression system prevents body weight gain by reducing adiposity in mice. DCL-knockdown slightly increased whole-body energy expenditure possibly as a result of elevated circulating thyroid hormones. In white adipose tissue (WAT) triglyceride uptake was increased while the average adipocyte cell size was reduced. At histological level we observed clear signs of browning, and thus increased thermogenesis in WAT. We found no indications for stimulated thermogenesis in brown adipose tissue (BAT). Altogether, we demonstrate an important, though subtle, role of tanycytic DCL in body weight control through regulation of energy expenditure, and specifically WAT browning. Elucidating mechanisms underlying the role of DCL in regulating brain-peripheral crosstalk further might identify new treatment targets for obesity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/378/1341 / 692/163/2743 / Adipose tissue / Adipose tissue (brown) / Adipose Tissue - metabolism / Adipose Tissue, Brown - metabolism / Adipose Tissue, White - metabolism / Adiposity - genetics / Animals / Antibiotics / Body fat / Body size / Body Weight / Body weight control / Body weight gain / Capillaries / Cell size / Central nervous system / Cerebrospinal fluid / Doublecortin Domain Proteins / Doublecortin protein / Doublecortin-like / Doxycycline / Energy expenditure / Energy Metabolism / Gene Knockdown Techniques / Hormones / Humanities and Social Sciences / Hypothalamus / Male / Mice / Mice, Inbred C57BL / multidisciplinary / Neuroplasticity / Obesity / Obesity - genetics / Obesity - metabolism / Science / Science (multidisciplinary) / Tanycytes / Thermogenesis / Thermogenesis - genetics / Thyroid / Thyroid hormones / Weight control / White adipose tissue browning / β-Tanycytes