Loss of the centrosomal protein Cenpj leads to dysfunction of the hypothalamus and obesity in mice

• Published in: Science China. Life sciences Vol. 64; no. 3; pp. 419 - 433
• Main Authors: Ding, Wenyu, Zhang, Changjiang, Wang, Baisong, Zhou, Xin, Sun, Le, Zhong, Suijuan, Liu, Jing, Zhang, Junjing, Wang, Xiaoqun, Wu, Qian
• Format: Journal Article
• Language: English
• Published: Beijing Science China Press 01.03.2021; Springer Nature B.V
• Subjects: Animals; Apoptosis; Arcuate nucleus; Biomedical and Life Sciences; Body weight; Cell Line; Cell Proliferation; Centrosomes; Cerebral cortex; Cilia; Diabetes mellitus (non-insulin dependent); Embryos; Gene Knockdown Techniques; Hypothalamus; Hypothalamus - embryology; Hypothalamus - metabolism; Hypothalamus - physiopathology; Insulin; Insulin resistance; Life Sciences; Melanocortin; Melanocortin MC4 receptors; Mice; Microtubule-Associated Proteins - genetics; Neurogenesis; Neurons - metabolism; Neuropeptide Y; Obesity; Obesity, Morbid - genetics; Obesity, Morbid - physiopathology; Paraventricular nucleus; Pro-Opiomelanocortin - metabolism; Proopiomelanocortin; Proteins; Receptor, Melanocortin, Type 4 - metabolism; Research Paper; Thyroid Nuclear Factor 1 - genetics; Thyroid transcription factor 1; Cenpj; arcuate nucleus; centrosomal protein; hypothalamus; Nkx2.1; paraventricular nucleus
• ISSN: 1674-7305; 1869-1889; 1869-1889
• DOI: 10.1007/s11427-020-1767-5

Cenpj is a centrosomal protein located at the centrosomes and the base of cilia, it plays essential roles in regulating neurogenesis and cerebral cortex development. Although centrosomal and cilium dysfunction are one of the causes of obesity, insulin resistance, and type 2 diabetes, the role that Cenpj plays in the regulation of body weight remains unclear. Here, we deleted Cenpj by crossing Cenpj flox/flox mice with Nkx2.1-Cre mice. Loss of the centrosomal protein Cenpj in Nkx2.1-expressing cells causes morbid obesity in mice at approximately 4 months of age with expended brain ventricles but no change of brain size. We found that hypothalamic cells exhibited reduced proliferation and increased apoptosis upon Cenpj depletion at the embryonic stages, resulting in a dramatic decrease in the number of Proopiomelanocortin (POMC) neurons and electrophysiological dysfunction of NPY neurons in the arcuate nucleus (ARC) in adults. Furthermore, depletion of Cenpj also reduced the neuronal projection from the ARC to the paraventricular nucleus (PVN), with decreased melanocortin-4 receptors (MC4R) expression in PVN neurons. The study defines the roles that Cenpj plays in regulating hypothalamus development and body weight, providing a foundation for further understanding of the pathological mechanisms of related diseases.