Elsevier

The Lancet Neurology

Volume 16, Issue 6, June 2017, Pages 465-477
The Lancet Neurology

Review
Neurological consequences of obesity

https://doi.org/10.1016/S1474-4422(17)30084-4Get rights and content

Summary

The high prevalence of obesity is associated with an enormous medical, social, and economic burden. The metabolic dysfunction, dyslipidaemia, and inflammation caused by obesity contribute to the development of a wide variety of disorders and effects on the nervous system. In the CNS, mild cognitive impairment can be attributed to obesity-induced alterations in hippocampal structure and function in some patients. Likewise, compromised hypothalamic function and subsequent defects in maintaining whole-body energy balance might be early events that contribute to weight gain and obesity development. In the peripheral nervous system, obesity-driven alterations in the autonomic nervous system prompt imbalances in sympathetic–parasympathetic activity, while alterations in the sensory–somatic nervous system underlie peripheral polyneuropathy, a common complication of diabetes. Pharmacotherapy and bariatric surgery are promising interventions for people with obesity that can improve neurological function. However, lifestyle interventions via dietary changes and exercise are the preferred approach to combat obesity and reduce its associated health risks.

Introduction

About 2·1 billion individuals are overweight or obese.1 Genetic background predisposes certain individuals and ethnicities to develop obesity;2 however, weight gain is largely driven by factors that arose in high-income countries in the late 20th century.3 This obesogenic environment is attributable to several factors, including the overconsumption of processed, affordable, heavily marketed, highly palatable, and energy-dense foods combined with an increased sedentary lifestyle. Although there are indications that the exponential increase in obesity incidence has plateaued in high-income countries, numerous regions worldwide that have adopted the lifestyle of a high-income society continue to show an increase in obesity incidence, which then gets reflected in a worldwide increase.1 Projections estimate that more than 18% of adults will be obese by 2025.4

Defined as an increase of fat mass that adversely affects health, obesity is a risk factor for cardiovascular disease and certain cancers (panel 1). Central obesity, which is accompanied by a low-grade metabolic inflammation in visceral adipose tissue, is also recognised as both a component and a driver of the metabolic syndrome.8 The metabolic syndrome is characterised by the presence of multiple comorbidities, including dyslipidaemia, decreased insulin sensitivity, hyperinsulinaemia, hyperglycaemia, and hypertension; thus, obesity is an underlying promoter of systemic metabolic dysfunction. Multiple tissues, including those of the liver, pancreas, kidney, and the vasculature, exhibit dysfunction as a consequence of obesity. Accumulating evidence also links obesity with several neurological disorders. Although the CNS and the peripheral nervous system (PNS) are quite distinct in form and function, both are susceptible to obesity-driven dysfunction, suggesting that common mechanisms might be enabled by visceral adiposity. Obesity drives components of the metabolic syndrome that are strongly linked to neurological deficits (eg, strong associations exist between insulin resistance and cognitive decline). As a result, multiple mechanisms might be interacting to culminate in neurological dysfunction, but ascertaining direct causality of visceral adiposity on neurological complications is challenging.

Mechanistic insights provided by animal models of obesity suggest that excess dietary fat compromises the hypothalamic control of energy homoeostasis. This mechanism might contribute to adipose tissue dysfunction, leading to elevated concentrations of free fatty acids and systemic dyslipidaemia. Chronic caloric excess affects multiple organs, including the liver, and leads to an increase in circulating triglycerides. This dyslipidaemia can result in free fatty acids-induced lipotoxicity, and changes in intracellular signalling or lipid use that can result in neurological dysfunction. Although these mechanisms are likely to affect the CNS and PNS in a multifactorial fashion, recent advances have improved our insight into the neurological complications that can occur with obesity. In this Review, we outline the pathophysiological development of obesity and dyslipidaemia, describe diseases of the CNS and PNS that can arise as a consequence, present evidence for lipotoxicity and metabolic inflammation as the principal mechanisms underlying these neurological consequences of obesity, and discuss potential treatment approaches.

Section snippets

The pathophysiology of obesity

The adipose tissue performs functions that include the storage and release of energy, thermal insulation, and protection of internal organs from trauma. Additionally, the adipose tissue possesses endocrine activity that is mediated by adipokines, a diverse set of signalling molecules that includes hormones, cytokines, acute phase reactants, and growth factors. These molecules are essential in regulating metabolically active tissues and organs involved in maintaining energy homoeostasis, such as

Effects of obesity on the CNS

Accumulating evidence indicates that obesity adversely affects the CNS and, in particular, cognitive function. For example, meta-analyses have shown a strong association between obesity and neurological disorders, such as Alzheimer's disease and other dementias.13, 14 Epidemiological evidence indicates that obesity doubles the risk of Alzheimer's disease when compared with that of individuals of healthy bodyweight,13 and that a higher body-mass index (BMI) in midlife predicts greater risk of

Effects of obesity in the PNS

The PNS is divided into the autonomic nervous system, with the sympathetic and parasympathetic divisions, and the somatic nervous system, composed of the sensory and motor peripheral nerves. The autonomic and sensory ganglia, along with unmyelinated fibres and synaptic terminals of the PNS are not protected by the blood–brain barrier, and are therefore susceptible to the pathophysiological consequences of obesity.

The autonomic nervous system plays a crucial role in regulating energy balance

Neurological benefits of targeting obesity

Because obesity and dyslipidaemia can provoke highly morbid neurological consequences (panel 2), the optimal therapy is to target obesity itself. Lifestyle interventions, consisting of dietary modifications combined with exercise, provide an accessible and inexpensive strategy that is effective in combating obesity and restoring neurological function (table 3). The physiological benefits of lifestyle interventions, which are greatest when dietary and exercise regimens are used in concert,

Conclusions and future directions

Although extensive data exist to support obesity as a mediator of CNS and PNS injury, the ideal intervention to prevent associated cognitive impairment, autonomic neuropathy, and polyneuropathy is not known. Future studies are needed to determine the comparative effectiveness of pharmacological weight loss, surgical weight loss, and exercise interventions using rigorous study designs and patient-oriented outcomes. These studies will also have to evaluate the cost-effectiveness of these

Search strategy and selection criteria

We searched PubMed and Google Scholar for articles published in English from Nov 2, 2015, to July 1, 2016, and examined original research articles and review articles. The following terms were used in various combinations: “obesity”, “dyslipidemia”, “adipose”, “adipocyte”, “inflammation”, “brain”, “Alzheimer's disease”, “cognitive impairment”, “hypothalamus”, “hippocampus”, “high fat diet”, “autonomic nervous system”, “peripheral nervous system”, “peripheral neuropathy”, “lifestyle

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