Pathophysiology of Neurogenic Obesity After Spinal Cord Injury

Abstract

Individuals with a spinal cord injury (SCI) have a unique physiology characterized by sarcopenia, neurogenic osteoporosis, neurogenic anabolic deficiency, sympathetic dysfunction, and blunted satiety associated with their SCI, all of which alter energy balance and subsequently body composition. The distinct properties of "neurogenic obesity" place this population at great risk for metabolic dysfunction, including systemic inflammation, hyperglycemia, dyslipidemia, and hypertension. The purpose of this article is to demonstrate the relationship between neurogenic obesity and the metabolic syndrome after SCI, highlighting the mechanisms associated with adipose tissue pathology and those respective comorbidities. Additionally, representative studies of persons with SCI will be provided to elucidate the severity of the problem and to prompt greater vigilance among SCI specialists as well as primary care providers in order to better manage the epidemic from a public health perspective.

Keywords: dyslipidemia; glucose intolerance; hypertension; metabolic syndrome; obesity; spinal cord injury.

Figure 1.

Pathophysiology of obesity and metabolic syndrome. Environmental factors influence gene expression inducing gain of adipose tissue (AT). When subcutaneous adipose tissue capacity is reached, free-fatty acids (FFA) mobilize and are deposited in visceral and ectopic fat (e.g., liver, skeletal muscle, and heart). FFA deposition in muscle inhibits insulin-mediated glucose uptake (i.e., insulin resistance, IR), which reduces lipolysis and increases nonesterified FFA flux to the liver, resulting in hepatic IR (enhancing gluconeogenesis), hepatic lipogenesis, and atherogenic dyslipidemia. Hepatic glucagon resistance to amino acid (AA) production reduces ureagenesis, resulting in hyperaminoacidemia and glucagon resistance (GR); increased glucagon production from pancreatic α-cells accelerates hepatic gluconeogenesis. FFA deposit in the pancreas where β-cell dysfunction is caused by lipotoxicity; hyperglycemia and IR results. Hyperinsulinemia stimulates sodium reabsorption and increased sympathetic nervous system activity, contributing to hypertension (HTN). AT becomes more IR and releases proinflammatory adipokines, decreasing the anti-inflammatory adiponectin. Triglycerides and toxic metabolites in the liver induce lipotoxicity, mitochondrial dysfunction, and endoplasmic reticulum stress, resulting in hepatic damage, apoptosis, and fibrosis (nonalcoholic liver disease, NAFLD). The damaged hepatocytes release dipeptidyl peptidase 4 (DPP4), which stimulates AT macrophage inflammation, promoting further IR. Adapted from Godoy-Matos AF, Silva Junior WS, Valerio CM. NAFLD as a continuum: From obesity to metabolic syndrome and diabetes. Diabetol Metab Syndr. 2020;12:60. https://doi.org/10.1186/s13098-020-00570-y, licensed under a Creative Commons Attribution 4.0 International License: https://creativecommons.org/licenses/by/4.0/.