Loss of hypothalamic MCH decreases food intake in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is associated with impaired energy metabolism, including weight loss and decreased appetite which are negatively correlated with survival. Neural mechanisms underlying metabolic impairment in ALS remain unknown. ALS patients and presymptomatic gene carriers have early hypothalamic atrophy. The lateral hypothalamic area (LHA) controls metabolic homeostasis through the secretion of neuropeptides such as orexin/hypocretin and melanin-concentrating hormone (MCH). Here, we show loss of MCH-positive neurons in three mouse models of ALS based on SOD1 or FUS mutations. Supplementation with MCH (1.2 µg/d) through continuous intracerebroventricular delivery led to weight gain in male mutant Sod1G86R mice. MCH supplementation increased food intake, rescued expression of the key appetite-related neuropeptide AgRP (agouti-related protein) and modified respiratory exchange ratio, suggesting increased carbohydrate usage during the inactive phase. Importantly, we document pTDP-43 pathology and neurodegeneration in the LHA of sporadic ALS patients. Neuronal cell loss was associated with pTDP-43-positive inclusions and signs of neurodegeneration in MCH-positive neurons. These results suggest that hypothalamic MCH is lost in ALS and contributes to the metabolic changes, including weight loss and decreased appetite.

The role of 5-HT2B receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors.

BACKGROUND AND PURPOSE: Valvular heart disease (VHD) is highly prevalent in industrialized countries. Chronic use of anorexigens, amphetamine or ergot derivatives targeting the 5-HT system is associated with VHD. Here, we investigated the contribution of 5-HT receptors in a model of valve degeneration induced by nordexfenfluramine, the main metabolite of the anorexigens, dexfenfluramine and benfluorex. EXPERIMENTAL APPROACH: Nordexfenfluramine was infused chronically (28 days) in mice ((WT and transgenic Htr2B -/- , Htr2A -/- , and Htr2B/2A -/- ) to induce mitral valve lesions. Bone marrow transplantation was also carried out. Haemodynamics were measured with echocardiography; tissues and cells were analysed by histology, immunocytochemistry, flow cytometry and RT -qPCR. Samples of human prolapsed mitral valves were also analysed. KEY RESULTS: Chronic treatment of mice with nordexfenfluramine activated 5-HT2B receptors and increased valve thickness and cell density in a thick extracellular matrix, mimicking early steps of mitral valve remodelling. Lesions were prevented by 5-HT2A or 5-HT2B receptor antagonists and in transgenic Htr2B -/- or Htr2A/2B -/- mice. Surprisingly, valve lesions were mainly formed by numerous non-proliferative CD34+ endothelial progenitors. These progenitors originated from bone marrow (BM) as revealed by BM transplantation. The initial steps of mitral valve remodelling involved mobilization of BM-derived CD34+ CD31+ cells by 5-HT2B receptor stimulation. Analysis of human prolapsed mitral valves showing spontaneous degenerative lesions, demonstrated the presence of non-proliferating CD34+ /CD309+ /NOS3+ endothelial progenitors expressing 5-HT2B receptors. CONCLUSIONS AND IMPLICATIONS: BM-derived endothelial progenitor cells make a crucial contribution to the remodelling of mitral valve tissue. Our data describe a new and important mechanism underlying human VHD.