# Surgical removal of visceral adipose tissue has therapeutic benefit in male APPNL-F mice

## TL;DR

Removing visceral fat in male Alzheimer's mice improved metabolism and memory, but effects varied by sex and disease stage.

## Contribution

Demonstrates sex-specific metabolic and cognitive benefits of visceral fat removal in a mouse model of Alzheimer's disease.

## Key findings

- Symptomatic male mice showed improved glucose metabolism and memory after visceral fat removal.
- Female mice experienced visceral fat reaccumulation due to increased lipogenesis.
- Sex-specific differences in lipid and glucose metabolism explain divergent outcomes after visceral fat removal.

## Abstract

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 pro-inflammatory cytokines. We hypothesized that VFR removal in AD mice would improve metabolism and cognition.

Male and female APPNL-F mice underwent sham or vWAT surgical resection (periovarian or 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.

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.

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.

Infographic comparing metabolic and molecular effects of visceral fat removal in pre-symptomatic and symptomatic female (top, pink background) and male (bottom, blue background) models, with icons representing fat balance, weight, blood glucose, adipocyte markers, liver metabolism, and brain changes; arrows and symbols indicate direction of molecular changes and biological pathways including genes, hormones, and processes such as lipogenesis, glycolysis, and inflammation.