Weight loss aggravates obesity-induced hypothalamic inflammation in mid-aged mice

Area of Science:

• Neuroscience
• Metabolic Research
• Aging Studies

Background:

• Neuroinflammation is linked to weight gain and aging.
• The early hypothalamic response to weight loss (WL) in mid-aged individuals is not well understood.
• Investigating the role of hypothalamic microgliosis resolution in WL-induced normoglycemia is crucial.

Purpose of the Study:

• To determine if WL-induced normoglycemia in mid-aged mice is mediated by resolving hypothalamic microgliosis.
• To compare the transcriptomic and microglial responses to WL in mid-aged versus young mice.
• To assess the relationship between hypothalamic changes, adipose tissue inflammation, and glucose tolerance.

Main Methods:

• Mid-aged and young mice were fed normal chow (NC) or high-fat diet (HFD) for 8 weeks.
• Weight loss was induced by switching to NC for 2 weeks.
• Whole-hypothalamus RNA sequencing, microglial morphology analysis, and glucose tolerance tests were performed.

Main Results:

• Weight loss in mid-aged mice aggravated hypothalamic transcriptomic changes and microglial activation (increased cell volume and pNFκB staining) compared to HFD alone.
• Despite aggravated hypothalamic changes, mid-aged mice achieved full normalization of glucose tolerance.
• Adipose tissue inflammation persisted post-weight loss and correlated with hypothalamic microglial volume.

Conclusions:

• In mid-aged mice, early weight loss exacerbates obesity-induced hypothalamic and microglial changes.
• Normalization of glucose intolerance during early weight loss does not depend on resolving these hypothalamic and microglial alterations.
• Adipose tissue inflammation may be linked to persistent hypothalamic neuroinflammation during weight loss.