Effect of thermoneutral housing on MASLD severity, hepatic gene expression, and BAT activation during beta3-adrenergic stimulation in mice

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), and its more advanced stage metabolic dysfunction-associated steatohepatitis, is the most common chronic liver disease, constituting a major public health issue. No medication is approved for MASLD treatment, and relevant preclinical models are needed to define molecular mechanisms underlying MASLD pathogenesis, and evaluate therapeutic approaches. Here we demonstrated that compared to standard temperature housing, thermoneutral housing aggravated western diet (WD)-induced obesity, diabetes, and steatosis in male mice, which was associated with increased hepatic expression of inflammation- and fibrosis-related genes. Accordingly, compared to standard-housed mice, thermoneutral-housed WD-fed mice developed more severe hepatic inflammation and fibrosis. The liver is the central metabolic organ in whole-body metabolic homeostasis. We used thermoneutrally housed mice with WD-induced MASLD to examine the effect of MASLD during {beta}3- adrenergic stimulation, and found that diet-induced MASLD was associated with defective inter- organ metabolic cross-talk, leading to impaired brown adipose tissue activation. HighlightsO_LIThermoneutral housing promotes WD-induced obesity and MASLD in mice C_LIO_LIThermoneutral housing fosters WD-induced change in gene expression C_LIO_LIThermoneutral housing fosters hepatic inflammation and fibrosis C_LIO_LIMASLD is associated with defective BAT response to {beta}3-adrenergic stimulation C_LI