Loss of hypothalamic MCH decreases food intake in amyotrophic lateral sclerosis

Abstract

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.

Abnormal energy metabolism in ALS: a key player?

“…It senses and integrates internal signals to adapt food intake and energy expenditure [3]. Histopathological analysis of the hypothalamus of ALS patients showed TDP-43 inclusions [19,20,21 && ], while imaging techniques revealed marked atrophy and disrupted connectivity [20,22,23,24,25 & ,26]. These changes are also present in presymptomatic ALS gene carriers and correlate with lower BMI in ALS patients, suggesting a potential involvement in weight loss [19,22,25 ].…”

Angiostrongylus cantonensis induces energy imbalance and dyskinesia in mice by reducing the expression of melanin-concentrating hormone

“…Recent discoveries indicate a significant association between MCH system abnormalities and certain central nervous system disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), infectious encephalitis, and amyotrophic lateral sclerosis [ 21 – 24 ]. MCH administration in animal models is primarily conducted through intracerebroventricular injection and intranasal delivery, with the latter being a noninvasive route that circumvents the blood–brain barrier, enabling direct drug delivery from the nasal cavity to the brain.…”

Volume loss in the left anterior‐superior subunit of the hypothalamus in amyotrophic lateral sclerosis

“… 15 Metabolic dysfunction underlying ALS is still not understood at the neural mechanism level. 16 However, emerging findings suggest that the hypothalamus, which is responsible for regulating sleep–wake cycles, is involved in the development of ALS‐associated sleep problems. 11 Moreover, the hypothalamus acts as a hub for a vast network of neural circuits that regulate food‐related behavior.…”

“…The integrity of the hypothalamus is critical, as even the pre‐symptomatic stages of genetic ALS variants with hexanucleotide expansion of chromosome 9 open reading frame 72 (C9orf72) show hypothalamic atrophy, which is believed to contribute to the metabolic and autonomic disturbances of the disease 15 . Metabolic dysfunction underlying ALS is still not understood at the neural mechanism level 16 . However, emerging findings suggest that the hypothalamus, which is responsible for regulating sleep–wake cycles, is involved in the development of ALS‐associated sleep problems 11 .…”