Liver androgen receptor knockout attenuates high-fructose diet-induced glucose dysregulation in female mice

The Western diet, rich in fats and sugars such as fructose, contributes significantly to the global rise in obesity and type 2 diabetes mellitus. Although both high-fat diets (HFD) and high-fructose diets (HFrD) are known to impair hepatic insulin signaling, the specific mechanisms and potential sex-specific differences remain underexplored. Moreover, the role of hepatic androgen receptor (AR) in modulating these effects, particularly in females, has not been fully elucidated. Here, we investigated the contribution of hepatic AR to HFrD-induced metabolic dysfunction using liver-specific AR knockout (LivARKO) mice of both sexes. Male and female LivARKO and wild-type (WT) littermates were subjected to either a HFrD or calorie-matched control diet from 4 to 12 wk of age and underwent several metabolic tests during <i>months 1</i> and <i>2</i>. Glucose tolerance tests (GTT) conducted during <i>month 1</i> revealed that WT-HFrD females developed significant glucose intolerance, whereas LivARKO-HFrD females exhibited partial protection, demonstrating improved glucose clearance relative to their WT counterparts. These effects appeared sex-specific, as male LivARKO mice did not exhibit similar protective effects under HFrD conditions. Our findings suggest that hepatic AR plays a sex-specific role in mediating fructose-induced insulin resistance, and its deletion in females confers partial protection against diet-induced metabolic impairments by improving hepatic insulin signaling and regulating gluconeogenic genes. This highlights the importance of considering sex and hepatic androgen signaling in the development of targeted therapies for diet-induced metabolic disorders.<b>NEW & NOTEWORTHY</b> To our knowledge, this study is the first to demonstrate that liver-specific androgen receptor (AR) deletion in female mice provides selective protection against fructose-induced insulin resistance. Although hepatic AR loss improves insulin sensitivity, it does not fully preserve insulin secretion or gluconeogenic control, revealing a sex-specific, dichotomous role of hepatic AR in metabolic regulation. These findings highlight hepatic AR as a potential therapeutic target for diet- and androgen-related metabolic dysfunction in females.