The mitigation of activity-based anorexia by obese adipose tissue transplant is abolished by neonatal AgRP neuron ablation

Abstract Anorexia nervosa (AN) is an eating disorder observed primarily in girls and women, and is characterized by a low body weight, hypophagia, and hyperactivity. The activity-based anorexia (ABA) paradigm models aspects of AN, and refers to the progressive weight loss, hypophagia, and hyperactivity developed by rodents subjected to fixed-time food restriction and running wheel access. Recent metabolic studies identified white adipose tissue (WAT) as a primary location of the ‘metabolic memory’ of prior obesity, and implicated WAT-derived signals as drivers of relapse to obesity following weight loss. Thus, we examined whether an obese WAT transplant could attenuate ABA-induced weight loss in normal female mice. Recipient mice received a WAT transplant harvested from either standard chow-fed, or high-fat diet (HFD)-fed obese mice. Obese fat recipient (OFR) and control fat recipient (CFR) mice were then tested for ABA. OFR mice “survived” longer than CFR mice in the ABA paradigm, defined as maintaining 75% of their initial body weight. Next, we tested whether agouti-related peptide (AgRP) neurons, which regulate feeding-related behaviors and metabolism, mediate obese WAT transplant-induced resilience against ABA. CFR and OFR mice received either control or neonatal AgRP ablation, and were assessed for ABA. OFR intact mice maintained higher body weights than CFR intact mice during ABA, but this effect was abolished by neonatal AgRP ablation. Furthermore, ablation reduced survival in OFR, but not CFR mice. In summary, obese WAT transplants signal to AgRP neurons to protect against ABA. Obese WAT-derived factors may provide targets for treatment development in AN.