RESUMO
Retinoic acid-induced 1 (RAI1) haploinsufficiency causes Smith-Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural Rai1 to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (BDNF) and its downstream signalling are disrupted in SMS (Rai1+/-) mice. Selective Rai1 loss from all BDNF-producing cells or from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that Rai1 ablation decreased the intrinsic excitability of PVHBDNF neurons. Chronic treatment of SMS mice with LM22A-4 engages neurotrophin downstream signalling and delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that RAI1 regulates body weight and metabolic function through hypothalamic BDNF-producing neurons and that targeting neurotrophin downstream signalling might improve associated SMS phenotypes.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Síndrome de Smith-Magenis , Transativadores , Fatores de Transcrição , Animais , Camundongos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Homeostase , Hipotálamo/metabolismo , Neurônios/metabolismo , Obesidade/genética , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Crescimento Neural/metabolismo , Peso CorporalRESUMO
Colonic duplication is a very rare congenital anomaly that is usually detected in infancy and early childhood. In the English literature, 6 cases of Y-shaped colonic duplication have been reported since 1953. We conducted a review of the reported cases, and we present a new case of a Y-shaped duplication of the sigmoid colon manifesting as long-term abdominal pain and constipation.