Activity-Based Anorexia Induces Browning of Adipose Tissue Independent of Hypothalamic AMPK

Abstract

Anorexia nervosa (AN) is an eating disorder leading to malnutrition and, ultimately, to energy wasting and cachexia. Rodents develop activity-based anorexia (ABA) when simultaneously exposed to a restricted feeding schedule and allowed free access to running wheels. These conditions lead to a life-threatening reduction in body weight, resembling AN in human patients. Here, we investigate the effect of ABA on whole body energy homeostasis at different housing temperatures. Our data show that ABA rats develop hyperactivity and hypophagia, which account for a massive body weight loss and muscle cachexia, as well as reduced uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), but increased browning of white adipose tissue (WAT). Increased housing temperature reverses not only the hyperactivity and weight loss of animals exposed to the ABA model, but also hypothermia and loss of body and muscle mass. Notably, despite the major metabolic impact of ABA, none of the changes observed are associated to changes in key hypothalamic pathways modulating energy metabolism, such as AMP-activated protein kinase (AMPK) or endoplasmic reticulum (ER) stress. Overall, this evidence indicates that although temperature control may account for an improvement of AN, key hypothalamic pathways regulating thermogenesis, such as AMPK and ER stress, are unlikely involved in later stages of the pathophysiology of this devastating disease.

The BDNF Val66Met Polymorphism Does Not Increase Susceptibility to Activity-Based Anorexia in Rats

“…Moreover, these results demonstrate that the thermogenic capacity of interscapular BAT was unchanged by 66Met; however, based on this study it may be premature to conclude that energy expenditure and metabolic function are not influenced by possession of this allelic substitution. It is possible that changes in muscle and/or white adipose tissue (WAT) function contribute to metabolic outcomes of 66Met in ABA rats, considering that physical exercise alters WAT morphology in BDNF Met/Met mice [53] and that exposure to ABA conditions has been shown to increase UCP1 expression in WAT depots [54]. Taken together, these outcomes indicate that the BDNF Val68Met polymorphism in rats does not influence feeding or body weight under normal conditions or when exposed to the ABA paradigm, and suggest that other tissue types could be examined for analysis of energy expenditure in future studies.…”

Obesity induces resistance to central action of BMP8B through a mechanism involving the BBSome

“…For the hematoxylin–eosin processing, the WAT sections were first stained with hematoxylin for 5 min, washed and stained again with eosin for 1 min. Detection of UCP1 in WAT was performed using anti-UCP1 antibody (1:500; ab10983) ( Abcam , Cambridge, UK) [ 27 , 29 , 31 , 32 , [35] , [36] , [37] ]. Images were taken with an Olympus XC50 digital camera ( Olympus Corporation ; Tokyo, Japan) at 20X.…”

“…Images were taken with an Olympus XC50 digital camera ( Olympus Corporation ; Tokyo, Japan) at 20X. Digital images for WAT were quantified with ImageJ 1.44 software ( National Institutes of Health ; Bethesda, MD, USA) [ 27 , 29 , 31 , 32 , [35] , [36] , [37] ]. We used 6–8 animals per experimental group.…”

Understanding the Effects of Antipsychotics on Appetite Control

“…Anorexia nervosa (AN) is a serious eating disorder identified with intense loss of appetite, extreme weight loss, and tremendous concern about gaining weight ( 75 ). A model for aspects of AN can be explained in activity-based anorexia (ABA), which is characterized by weight loss, hypophagia, and unusual restlessness in rodents with access to restricted food and running wheels.…”

“…Hence, selective antagonism of D2 and/or D3 receptors have been shown to reduce ABA strongly. According to a recent study on ABA by Fraga et al ( 75 ), it has been indicated that ABA affects brown adipose tissue (BAT) and white adipose tissue (WAT) thermogenesis in significant ways. Moreover, ABA does not alter primary regulators of adipose tissue activity, such as hypothalamic AMPK or endoplasmic reticulum stress signaling, raising the question of whether dopaminergic signaling somehow affects thermogenesis that may play a role in the feeding behavior.…”