Neurological consequences of obesity

Abstract

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.

Figure 1. Neurological consequences of obesity: an overview

Increased caloric intake and decreased energy expenditure result in a net energy overload, leading to adipose tissue expansion (hyperplasia and hypertrophy). Sustained caloric excess in visceral adipose tissue activates resident adipose tissue macrophages, contributing to the development of adipose tissue dysfunction and metabolic inflammation. As a consequence, circulating FFAs rise, are lipotoxic to peripheral tissues, and contribute to the development of metabolic dyshomeostasis. High FFA flux into the liver increases vLDL-triglyceride production, further promoting dyslipidemia, while ectopic fat deposition in the muscle and pancreas promotes insulin resistance and pancreatic β-cell dysfunction, respectively. Collectively, these impairments lead to the MetS. Similarly, the CNS, ANS, and PNS are also detrimentally affected by obesity and obesity-induced metabolic dysfunction, which we hypothesize is driven by the lipotoxic effects of dyslipidemia and increased circulating FFA. In the CNS, dysfunction leads to MCI and Alzheimer’s disease while in the ANS and PNS, the end result is autonomic and peripheral neuropathy, respectively. FFA = free fatty acid. vLDL = very-low-density lipoprotein. TG = triglyceride. MCI = mild cognitive impairment. MetS = metabolic syndrome.

Figure 2. Neurological complications associated with obesity and dyslipidemia

A. Diet-induced hypothalamic function in the CNS. Located in the CNS, the hypothalamus is responsible for controlling global energy balance by monitoring metabolic homeostasis. Diet-derived saturated fatty acids (SFA) can enter the CNS via the median eminence and accumulate in the mediobasal hypothalamus. In response to SFA, resident hypothalamic microglia that protect against pathogenic species become activated, resulting in inflammation, gliosis and neuronal stress. Pro-inflammatory signaling in the arcuate nucleus is associated with the development of impaired leptin signaling in pro-opiomelanocortin (POMC) and Agouti-related peptide (AgRP) neurons that in turn can affect second order neurons that govern energy balance. Hypothalamic inflammation alters satiety control, thus increasing the risk of developing obesity. B. Overview of obesity-mediated PNS injury. As a consequence of obesity, increased levels of FFA lead to decreased neurotrophic support and increased neurodegeneration in peripheral nerves. Long-chain fatty acids and inflammatory mediators directly injure DRG neurons, C-fiber cutaneous nerve endings, and the blood-nerve-barrier. As the blood-nerve-barrier is increasingly compromised, axons and their associated Schwann cells become vulnerable to injury, leading to neurogenic inflammation, mitochondrial dysfunction and ER stress. In aggregate, these changes alter nerve function and structure, contributing to the development and progression of polyneuropathy. FFA = free fatty acids. SFA = saturated fatty acids. CNS = central nervous system. ARC = arcuate nucleus. POMC = pro-opiomelanocortin. AgRP = Agouti-related peptide. DRG = dorsal root ganglia. FFA = free fatty acid.