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.