Alterations in Leptin Signaling in Amyotrophic Lateral Sclerosis (ALS).

Agueda Ferrer-Donato,Ana Contreras,Laura M Frago,Carmen M Fernandez-Martos,Julie A Chowen

doi:10.3390/ijms221910305

Abstract

Leptin has been suggested to play a role in amyotrophic lateral sclerosis (ALS), a fatal progressive neurodegenerative disease. This adipokine has previously been shown to be associated with a lower risk of ALS and to confer a survival advantage in ALS patients. However, the role of leptin in the progression of ALS is unknown. Indeed, our understanding of the mechanisms underlying leptin’s effects in the pathogenesis of ALS is very limited, and it is fundamental to determine whether alterations in leptin’s actions take place in this neurodegenerative disease. To characterize the association between leptin signaling and the clinical course of ALS, we assessed the mRNA and protein expression profiles of leptin, the long-form of the leptin receptor (Ob-Rb), and leptin-related signaling pathways at two different stages of the disease (onset and end-stage) in TDP-43A315T mice compared to age-matched WT littermates. In addition, at selected time-points, an immunoassay analysis was conducted to characterize plasma levels of total ghrelin, the adipokines resistin and leptin, and metabolic proteins (plasminogen activator inhibitor type 1 (PAI-1), gastric inhibitory peptide (GIP), glucagon-like peptide 1 (GLP-1), insulin and glucagon) in TDP-43A315T mice compared to WT controls. Our results indicate alterations in leptin signaling in the spinal cord and the hypothalamus on the backdrop of TDP-43-induced deficits in mice, providing new evidence about the pathways that could link leptin signaling to ALS.

Highlights

Amyotrophic lateral sclerosis (ALS) is an irreversible neurodegenerative disorder characterized by the selective and progressive loss of upper and lower motor neurons of the cerebral cortex, brainstem, and spinal cord [1]
To determine the leptin expression profile in white adipose tissue (WAT), the primary source of leptin production, we first examined the levels of leptin mRNA in different phases of the disease in TDP-43A315T mice compared to age-matched WT littermates (Figure 1)
There was a significant to determine the leptin expression profile in WAT, the primary source of leptin production, we first examined the levels of leptin mRNA in different phases of the disease in TDP43A315T mice compared to age-matched WT littermates (Figure 1)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is an irreversible neurodegenerative disorder characterized by the selective and progressive loss of upper and lower motor neurons of the cerebral cortex, brainstem, and spinal cord [1]. Included amongst the underlying metabolic alterations in ALS is leptin, a polypeptide hormone secreted primarily by adipocytes that exerts an important role in regulating food intake and energy balance through actions in the brain [2,3]. In addition to its classical role in the neuroendocrine regulation of food intake, the existence of its receptors in extra-hypothalamic brain regions strongly suggests that leptin affects other biological processes. Leptin is reported to be involved in ALS [10]; our understanding of the underlying biological mechanisms of leptin’s actions in the pathogenesis of ALS is limited, both clinical and epidemiological studies support the concept that altered leptin levels contribute to the pathogenesis of ALS [11]. A greater understanding of leptin signaling in ALS is needed to determine whether leptin pathways are causally connected to ALS pathogenesis

Methods

Results

Discussion

Conclusion