# Inhibition of sulfotransferase SULT2B1 prevents obesity and insulin resistance by regulating energy expenditure and intestinal lipid absorption

## TL;DR

Blocking SULT2B1, an enzyme that modifies cholesterol, helps prevent obesity and insulin resistance by boosting energy use and reducing fat absorption in the gut.

## Contribution

This study identifies SULT2B1 as a novel target for combating obesity and metabolic syndrome through its regulation of energy expenditure and lipid absorption.

## Key findings

- Genetic removal of Sult2b1 in mice prevented obesity and insulin resistance.
- Loss of Sult2b1 increased energy expenditure and thermogenesis in brown fat.
- Sult2b1 deficiency reduced intestinal lipid absorption and fatty acid levels.

## Abstract

Obesity is a major risk factor for multiple metabolic diseases, including type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD). The cholesterol sulfotransferase SULT2B1 is best known for its function in converting cholesterol to cholesterol sulfate. Here, by using the high-fat diet (HFD)-induced obesity model and the genetic obese ob/ob mice, we showed that genetic ablation of Sult2b1 protected mice from developing obesity and related insulin resistance, hepatic steatosis, and adipose tissue inflammation. Loss of Sult2b1 increased energy expenditure without affecting food intake or locomotive activity. The cold exposure test revealed that loss of Sult2b1 promoted thermogenesis in brown adipose tissue, which may have contributed to increased energy expenditure. In vivo reconstitution experiments suggested that the loss of Sult2b1 in extrahepatic tissues might have been responsible for the metabolic benefit. Mechanistically, our in vivo lipid uptake and metabolomic analyses showed that the Sult2b1KO mice exhibited suppression of intestinal dietary lipid absorption and the consequent downregulation of both systemic fatty acid levels and fatty acid metabolism. Our results suggest that targeting SULT2B1 may represent a novel strategy to combat obesity and related metabolic syndrome.