The neuropathology of obesity: insights from human disease

Abstract

Obesity, a pathologic state defined by excess adipose tissue, is a significant public health problem as it affects a large proportion of individuals and is linked with increased risk for numerous chronic diseases. Obesity is the result of fundamental changes associated with modern society including overnutrition and sedentary lifestyles. Proper energy homeostasis is dependent on normal brain function as the master metabolic regulator which integrates peripheral signals, modulates autonomic outflow and controls feeding behavior. Therefore, many human brain diseases are associated with obesity. This review explores the neuropathology of obesity by examining brain diseases which either cause or are influenced by obesity. First, several genetic and acquired brain diseases are discussed as a means to understand the central regulation of peripheral metabolism. These diseases range from monogenetic causes of obesity (leptin deficiency, MC4R deficiency, Bardet-Biedl syndrome and others) to complex neurodevelopmental disorders (Prader-Willi syndrome and Sim1 deficiency) and neurodegenerative conditions (frontotemporal dementia and Gourmand’s syndrome) and serve to highlight the central regulatory mechanisms which have evolved to maintain energy homeostasis. Next, to examine the effect of obesity on the brain, chronic neuropathologic conditions (epilepsy, multiple sclerosis and Alzheimer’s disease) are discussed as examples of obesity leading to maladaptive processes which exacerbate chronic disease. Thus obesity is associated with multiple pathways including abnormal metabolism, altered hormonal signaling and increased inflammation which act in concert to promote downstream neuropathology. Finally, the effect of anti-obesity interventions is discussed in terms of brain structure and function. Together, understanding human diseases and anti-obesity interventions leads to insights into the bidirectional interaction between peripheral metabolism and central brain function, highlighting the need for continued clinicopathologic and mechanistic studies of the neuropathology of obesity.

Intermittent metabolic switching, neuroplasticity and brain health

“…In laboratory animals, IF (daily TRF or ADF) extends the average lifespan by up to 40% and protects against major chronic diseases, including cancer, diabetes and kidney disease 7 . Increasing evidence suggests that individuals with sedentary, overindulgent lifestyles are at increased risk of developing AD and PD, and animal studies support the notion that a chronic positive energy balance devoid of IMS renders the brain prone to AD and PD 131,132 . Conversely, exercise and moderation of energy intake reduce the risk of AD and PD 133,134 , and exercise intervention trials further suggest that IMS reduces clinical symptoms in many patients with AD and PD 135,136 .…”

Being overweight is associated with hippocampal atrophy: the PATH Through Life Study

“…4 However, an alternative explanation is that the effect of obesity in old age is partly masked by weight loss observable in clinical dementia and generally attributed to undernutrition. 30 This question has important implications for policy, health care and prevention and should receive particular attention in future research.…”

Metabolic and behavioral effects of mutant huntingtin deletion in Sim1 neurons in the BACHD mouse model of Huntington’s disease

“…Yet, the critical neuronal population in the hypothalamus responsible for this effect remains to be identified. Oxytocin and vasopressin expressing neurons in the PVN have been implicated in both emotional and metabolic control1718. We therefore hypothesized that expression of mutant HTT in PVN neurons would be critical for the development of the metabolic and psychiatric phenotypes in BACHD mice.…”