The anx/anx Mouse - A Valuable Resource in Anorexia Nervosa Research

Abstract

Animal models are invaluable resources in research concerning the neurobiology of anorexia nervosa (AN), to a large extent since valid clinical samples are rare. None of the existing models can capture all aspects of AN but they are able to mirror the core features of the disorder e.g., elective starvation, emaciation and premature death. The anorectic anx/anx mouse is of particular value for the understanding of the abnormal response to negative energy balance seen in AN. These mice appear normal at birth but gradually develops starvation and emaciation despite full access to food, and die prematurely around three weeks of age. Several changes in hypothalamic neuropeptidergic and -transmitter systems involved in regulating food intake and metabolism have been documented in the anx/anx mouse. These changes are accompanied by signs of inflammation and degeneration in the same hypothalamic regions; including activation of microglia cells and expression of major histocompatibility complex I by microglia and selective neuronal populations. These aberrances are likely related to the dysfunction of complex I (CI) in the oxidative phosphorylation system of the mitochondria, and subsequent increased oxidative stress, which also has been revealed in the hypothalamus of these mice. Interestingly, a similar CI dysfunction has been shown in leukocytes from patients with AN. In addition, a higher expression of the Neurotrophic Receptor Tyrosine Kinase 3 gene has been shown in the anx/anx hypothalamus. This agrees with AN being associated with specific variants of the genes for brain derived neurotrophic factor and Neurotrophic Receptor Tyrosine Kinase 2. The anx/anx mouse is also glucose intolerant and display pancreatic dysfunction related to increased levels of circulating free fatty acids (FFA) and pancreatic inflammation. An increased incidence of eating disorders has been reported for young diabetic women, and as well has increased levels of circulating FFAs in AN. Also similar to individuals with AN, the anx/anx mouse has reduced leptin and increased cholesterol levels in serum. Thus, the anx/anx mouse shares several characteristics with patients with AN, including emaciation, starvation, premature death, diabetic features, increased FFA and low leptin, and is therefore a unique resource in research on the (neuro)biology of AN.

Keywords: AGRP; anorexia; hypothalamus; inflammation; microglia; neurodegeneration; neuropeptide.

FIGURE 1

An anx/anx mouse and wildtype (+/+) littermate, age 17 days.