Surgical Removal of Visceral Adipose Tissue has Therapeutic Benefit in Male APPNL-F Mice

  1. Samuel A. McFadden
  2. Yimin Fang
  3. Kathleen Quinn
  4. Mackenzie R. Peck
  5. Jenelle E. Chapman
  6. Tiarra Hill
  7. Andrzej Bartke
  8. Erin R. Hascup
  9. Kevin N. Hascup
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Abstract

Purpose

Visceral white adipose tissue (vWAT) accumulation causes systemic inflammation, insulin resistance, metabolic syndrome, and senescent cell accumulation that are risk factors for Alzheimer’s disease (AD). Visceral fat removal (VFR) improves metabolism and reduces proinflammatory cytokines. We hypothesized that VFR removal in AD mice would improve metabolism and cognition.

Methods

Male and female APPNL-F mice underwent sham or vWAT surgical resection (epididymal and perirenal) at 4 (pre-symptomatic) and 16 (symptomatic) months of age to understand interventional and therapeutic effects, respectively. At 18 months of age, glucose metabolism and novel object recognition (NOR) memory were assayed followed by assessment of body composition and tissue-specific markers of metabolism, cell senescence, inflammation, or amyloid accumulation.

Results

Male and female APPNL-F mice showed distinct VFR responses. In pre-symptomatic males, increased vWAT lipolysis and hepatic lipogenesis led to ectopic liver lipid accumulation, with reduced adiponectin and leptin, elevated visfatin, and impaired glucose metabolism. Symptomatic males showed reduced vWAT lipogenesis, enhanced hepatic lipolysis, glycolysis, and glycogenesis, lowering liver lipids and improving insulin sensitivity. Only symptomatic males improved NOR, linked to elevated hippocampal learning and memory markers. Female vWAT reaccumulation was due to increased lipogenesis and lower lipolysis. Pre-symptomatic females had lower hepatic lipogenesis, while glycolysis and glycogenesis declined with disease progression. Hippocampal senescence and inflammation were elevated early in the disease that persisted symptomatically.

Conclusions

Sex-specific differences in glucose and lipid metabolism and lipid accumulation underlie the divergent responses to VFR in APPNL-F mice, with symptomatic males showing the only beneficial outcomes in metabolism and cognition.

Graphical Abstract

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Male and female APPNL-F mice exhibited distinct visceral fat responses to AD progression. In males, early disease stages were marked by vWAT lipolysis and hepatic lipid accumulation with metabolic dysfunction, while symptomatic stages showed a metabolic shift that improved insulin sensitivity and NOR performance. In contrast, females displayed progressive vWAT reaccumulation, reduced hepatic metabolism, and persistent hippocampal senescence and inflammation from early stages onward.

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