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Cholinergic Control of Inflammation, Metabolic Dysfunction, and Cognitive Impairment in Obesity-Associated Disorders: Mechanisms and Novel Therapeutic Opportunities.

ABSTRACT: Obesity and obesity-associated disorders have become world-wide epidemics, substantially increasing the risk of debilitating morbidity and mortality. A characteristic feature of these disorders, which include the metabolic syndrome (MetS) and type 2 diabetes, is chronic low-grade inflammation stemming from metabolic and immune dysregulation. Inflammation in the CNS (neuroinflammation) and cognitive impairment have also been associated with obesity-driven disorders. The nervous system has a documented role in the regulation of metabolic homeostasis and immune function, and recent studies have indicated the important role of vagus nerve and brain cholinergic signaling in this context. In this review, we outline relevant aspects of this regulation with a specific focus on obesity-associated conditions. We outline accumulating preclinical evidence for the therapeutic efficacy of cholinergic stimulation in alleviating obesity-associated inflammation, neuroinflammation, and metabolic derangements. Recently demonstrated beneficial effects of galantamine, a centrally acting cholinergic drug and cognitive enhancer, in patients with MetS are also summarized. These studies provide a rationale for further therapeutic developments using pharmacological and bioelectronic cholinergic modulation for clinical benefit in obesity-associated disorders.

SUBMITTER: Chang EH

PROVIDER: S-EPMC6460483 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Cholinergic Control of Inflammation, Metabolic Dysfunction, and Cognitive Impairment in Obesity-Associated Disorders: Mechanisms and Novel Therapeutic Opportunities.

Chang Eric H EH Chavan Sangeeta S SS Pavlov Valentin A VA

Frontiers in neuroscience 20190405

Obesity and obesity-associated disorders have become world-wide epidemics, substantially increasing the risk of debilitating morbidity and mortality. A characteristic feature of these disorders, which include the metabolic syndrome (MetS) and type 2 diabetes, is chronic low-grade inflammation stemming from metabolic and immune dysregulation. Inflammation in the CNS (neuroinflammation) and cognitive impairment have also been associated with obesity-driven disorders. The nervous system has a docum ...[more]

PMID: 31024226

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Project description:Importance:Evidence shows that sleep dysfunction and ?-amyloid (A?) deposition work synergistically to impair brain function in individuals with normal cognition, increasing the risk of developing dementia later in life. However, whether A? continues to play an integral role in sleep dysfunction after the onset of cognitive decline in individuals with dementia is unclear. Objective:To determine whether A? deposition in the brain is associated with subjective measures of sleep quality and cognition in elderly individuals with cognitive disorders. Design, Setting, and Participants:A nested survey study was conducted at the Cognitive Disorders and Comprehensive Alzheimer Disease Center of Thomas Jefferson University Hospital in Philadelphia, Pennsylvania. Participants included patients aged 65 years and older with cognitive disorders verified by neuropsychological testing. Eligible participants were identified from a referral center-based sample of patients who underwent fluorine 18-labeled florbetaben positron emission tomography imaging at Thomas Jefferson University Hospital as part of the multicenter Imaging Dementia-Evidence for Amyloid Scanning study. Data collection and analysis occurred between November 2018 and March 2019. Main Outcomes and Measures:Sleep quality was measured via responses to sleep questionnaires, A? deposition was measured via fluorine 18-labeled florbetaben positron emission tomography, and cognition was measured via Mini-Mental State Examination (MMSE) performance. Results:Of the 67 eligible participants, 52 (77.6%) gave informed consent to participate in the study. Of the 52 enrolled participants (mean [SD] age, 76.6 [7.4] years), 27 (51.9%) were women. Daytime sleepiness was associated with A? deposition in the brainstem (B?=?0.0063; 95% CI, 0.001 to 0.012; P?=?.02), but not MMSE performance (B?=?-0.01; 95% CI, -0.39 to 0.37; P?=?.96). The number of nocturnal awakenings was associated with A? deposition in the precuneus (B?=?0.11; 95% CI, 0.06 to 0.17; P?<?.001) and poor MMSE performance (B?=?-2.13; 95% CI, -3.13 to -1.13; P?<?.001). Mediation analysis demonstrated an indirect association between A? deposition and poor MMSE performance that relied on nocturnal awakenings as an intermediary (B?=?-3.99; 95% CI, -7.88 to -0.83; P?=?.01). Conclusions and Relevance:Nighttime sleep disruption may mediate the association between A? and cognitive impairment, suggesting that there is an underlying sleep-dependent mechanism that links A? burden in the brain to cognitive decline. Further elucidation of this mechanism may improve understanding of disease processes associated with A? accumulation.

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Dataset Information

Cholinergic Control of Inflammation, Metabolic Dysfunction, and Cognitive Impairment in Obesity-Associated Disorders: Mechanisms and Novel Therapeutic Opportunities.

Publications

Cholinergic Control of Inflammation, Metabolic Dysfunction, and Cognitive Impairment in Obesity-Associated Disorders: Mechanisms and Novel Therapeutic Opportunities.

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