The Significance of Hypothalamic Inflammation and Gliosis for the Pathogenesis of Obesity in Humans

Endocr Rev. 2023 Mar 4;44(2):281-296. doi: 10.1210/endrev/bnac023.


Accumulated preclinical literature demonstrates that hypothalamic inflammation and gliosis are underlying causal components of diet-induced obesity in rodent models. This review summarizes and synthesizes available translational data to better understand the applicability of preclinical findings to human obesity and its comorbidities. The published literature in humans includes histopathologic analyses performed postmortem and in vivo neuroimaging studies measuring indirect markers of hypothalamic tissue microstructure. Both support the presence of hypothalamic inflammation and gliosis in children and adults with obesity. Findings predominantly point to tissue changes in the region of the arcuate nucleus of the hypothalamus, although findings of altered tissue characteristics in whole hypothalamus or other hypothalamic regions also emerged. Moreover, the severity of hypothalamic inflammation and gliosis has been related to comorbid conditions, including glucose intolerance, insulin resistance, type 2 diabetes, and low testosterone levels in men, independent of elevated body adiposity. Cross-sectional findings are augmented by a small number of prospective studies suggesting that a greater degree of hypothalamic inflammation and gliosis may predict adiposity gain and worsening insulin sensitivity in susceptible individuals. In conclusion, existing human studies corroborate a large preclinical literature demonstrating that hypothalamic neuroinflammatory responses play a role in obesity pathogenesis. Extensive or permanent hypothalamic tissue remodeling may negatively affect the function of neuroendocrine regulatory circuits and promote the development and maintenance of elevated body weight in obesity and/or comorbid endocrine disorders.

Keywords: gliosis; hypothalamus; inflammation; magnetic resonance imaging; obesity; type 2 diabetes.

Publication types

  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Child
  • Cross-Sectional Studies
  • Diabetes Mellitus, Type 2* / complications
  • Gliosis / etiology
  • Gliosis / pathology
  • Humans
  • Hypothalamus
  • Inflammation
  • Insulin Resistance*
  • Male
  • Obesity / complications
  • Prospective Studies