Obesity is a global health problem with a broad set of comorbidities, such as malnutrition, metabolic syndrome, diabetes, systemic hypertension, heart failure, and kidney failure. This review describes recent findings of neuroimaging and two studies of cell density regarding the roles of overnutrition-induced hypothalamic inflammation in neurodegeneration. These studies provided consistent evidence of smaller cortical thickness or reduction in the gray matter volume in people with overweight and obesity; however, the investigated brain regions varied across the studies. In general, bilateral frontal and temporal areas, basal nuclei, and cerebellum are more commonly involved. Mechanisms of volume reduction are unknown, and neuroinflammation caused by obesity is likely to induce neuronal loss. Adipocytes, macrophages of the adipose tissue, and gut dysbiosis in overweight and obese individuals result in the secretion of the cytokines and chemokines that cross the blood-brain barrier and may stimulate microglia, which in turn also release proinflammatory cytokines. This leads to chronic low-grade neuroinflammation and may be an important factor for apoptotic signaling and neuronal death. Additionally, significant microangiopathy observed in rat models may be another important mechanism of induction of apoptosis. Neuroinflammation in neurodegenerative diseases (such as Alzheimer’s and Parkinson’s diseases) may be similar to that in metabolic diseases induced by malnutrition. Poor cognitive performance, mainly in executive functions, in individuals with obesity is also discussed. This review highlights the neuroinflammatory and neurodegenerative mechanisms linked to obesity and emphasizes the importance of developing effective prevention and treatment intervention strategies for overweight and obese individuals.