Despite recent leaps in modern medicine, progress in the treatment of neurological diseases remains slow. The near impermeable blood-brain barrier (BBB) that prevents the entry of therapeutics into the brain, and the complexity of neurological processes, limits the specificity of potential therapeutics. Moreover, a lack of etiological understanding and the irreversible nature of neurological conditions have resulted in low tolerability and high failure rates towards existing small molecule-based treatments. Neuropeptides, which are small proteinaceous molecules produced by the body, either in the nervous system or the peripheral organs, modulate neurological function. Although peptide-based therapeutics originated from the treatment of metabolic diseases in the 1920s, the adoption and development of peptide drugs for neurological conditions are relatively recent. In this review, we examine the natural roles of neuropeptides in the modulation of neurological function and the development of neurological disorders. Furthermore, we highlight the potential of these proteinaceous molecules in filling gaps in current therapeutics.

Significance: With obesity on the rise, there is a growing appreciation for intracellular lipid droplet (LD) regulation. Here, we show how saturated fatty acids (SFAs) reduce fat storage–inducing transmembrane protein 2 (FIT2)–facilitated, pancreatic β cell LD biogenesis, which in turn induces β cell dysfunction and death, leading to diabetes. This mechanism involves direct acylation of FIT2 cysteine residues, which then marks the FIT2 protein for endoplasmic reticulum (ER)–associated degradation. Loss of β cell FIT2 and LDs reduces insulin secretion, increases intracellular ceramides, stimulates ER stress, and exacerbates diet-induced diabetes in mice. While palmitate and stearate degrade FIT2, unsaturated fatty acids such as palmitoleate and oleate do not, results of which extend to nutrition and diabetes.

The central nervous system was classically perceived as anatomically and functionally independent from the other visceral organs. But in recent decades, compelling evidence has led the scientific community to place a greater emphasis on the role of gut microbes on the brain. Pathological observations and early gastrointestinal symptoms highlighted that gut dysbiosis likely precedes the onset of cognitive deficits in Alzheimer’s disease (AD) and Parkinson’s disease (PD) patients. The delicate balance in the number and functions of pathogenic microbes and alternative probiotic populations is critical in the modulation of systemic inflammation and neuronal health. However, there is limited success in restoring healthy microbial biodiversity in AD and PD patients with general probiotics interventions and fecal microbial therapies. Fortunately, the gut microflora is susceptible to long-term extrinsic influences such as lifestyle and dietary choices, providing opportunities for treatment through comparatively individual-specific control of human behavior. In this review, we examine the impact of restrictive diets on the gut microbiome populations associated with AD and PD. The overall evidence presented supports that gut dysbiosis is a plausible prelude to disease onset, and early dietary interventions are likely beneficial for the prevention and treatment of progressive neurodegenerative diseases.

The liver partakes as a sensor and effector of peripheral metabolic changes and a regulator of systemic blood and nutrient circulation. As such, abnormalities arising from liver dysfunction can influence the brain in multiple ways, owing to direct and indirect bilateral communication between the liver and the brain. Interestingly, altered bile acid composition resulting from perturbed liver cholesterol metabolism influences systemic inflammatory responses, blood-brain barrier permeability, and neuron synaptic functions. Furthermore, bile acids produced by specific bacterial species may provide a causal link between dysregulated gut flora and neurodegenerative disease pathology through the gut-brain axis. This review will cover the role of bile acids—an often-overlooked category of active metabolites—in the development of neurological disorders associated with neurodegeneration. Further studies into bile acid signaling in the brain may provide insights into novel treatments against neurological disorders.