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

While neuroinflammation is an established response to both weight gain and aging, the hypothalamic neuroinflammatory early response to weight loss (WL) remains unknown, particularly in mid-age. Here, we questioned whether WL-induced rapid restoration of normoglycemia is mediated by the resolution of hypothalamic microgliosis in mid-aged mice. Mid-aged (1 year) mice were fed normal chow (NC) or a high-fat diet (HFD, 8 weeks), and WL was induced by a 2-week switch back to NC. Key findings were compared to young (7 weeks) mice. Mid-aged WL mice lost within 2 weeks 54% of their excess body weight, somewhat less than young mice (68%). Whole-hypothalamus RNA sequencing revealed ~ 4 times more differentially expressed genes (DEGs) in mid-aged than in young mice (2419 vs. 670, respectively). Nevertheless, in both ages, WL did not reverse but rather aggravated the transcriptomic response to HFD in ~ 80% of DEGs, uncovering downregulated metabolic (oxidative phosphorylation, thermogenesis) and neurodegenerative pathways, particularly in mid-age. Consistently, in the arcuate nucleus (ARC), HFD-induced increase in microglial number and volume further increased in weight-losing mid-aged mice. Consistently, only in mid-aged mice, WL further increased HFD-induced mean single-microglial volume in ARC, corresponding to increased pNFκB-(p-p65) nuclear staining. Despite aggravated hypothalamic and microglial changes, mid-aged mice fully normalized impaired glucose tolerance by early WL. Adipose tissue inflammation was not resolved in mid-aged WL mice, and adipose tissue crown-like-structure density correlated with ARC microglial cell volume (Rho(ρ) = 0.691, p = 0.001). In conclusion, in mid-aged mice, obesity-induced hypothalamic and microglial changes were aggravated during the early response to WL. The resolution of these obesity-induced changes is not required for the normalization of glucose intolerance.