Evidence of hypothalamic degeneration in the anorectic <i>anx/anx</i> mouse

Nilsson, Ida; Thams, Sebastian; Lindfors, Charlotte; Bergstrand, A; Cullheim, Staffan; Hökfelt, Tomas; Johansen, Jeanette E.

doi:10.1002/glia.21075

Cited by 25 publications

(26 citation statements)

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“…In addition, the canonical pathways generated in our microarray analysis suggest that cell death and inflammatory processes occur in the hypothalamus of the anx/anx mouse. This finding is in agreement with previous studies suggesting inflammation and cell death in the anx/anx hypothalamus (10,15,35,36). The anx locus is still unknown.…”

Section: Discussionsupporting

confidence: 93%

“…Consequently, the increased hypothalamic ROS levels that we have observed in the anx/anx mouse could be causally involved in the initial starvation and anorectic phenotype of this model. In the longer perspective, a chronic overproduction of ROS could lead to the signs of oxidative stress and neuronal degeneration of both the orexigenic and anorexigenic arcuate neurons that we have previously observed in the anx/anx mouse (7,15). In addition, the canonical pathways generated in our microarray analysis suggest that cell death and inflammatory processes occur in the hypothalamus of the anx/anx mouse.…”

Section: Discussionmentioning

confidence: 57%

“…In the anx/anx mouse, the orexigenic AGRP system develops normally until P12, after which the normal, continuous increase in AGRP-ir fiber density in the main projection areas ceases, and in some areas even decreases. These changes overlap both temporally and spatially with activation of microglia (10) and expression of MHC class I gene (H2-D b ) by both neurons and glia cells (15). In addition, we have shown increased amounts of apoptotic cells and presence of activated caspase 6 in NPY-ir fibers in the hypothalamus of these mice, indicating degenerative processes (15).…”

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confidence: 52%

“…One group coexpresses the two orexigenic neuropeptides neuropeptide Y (NPY) and agoutigene related protein (AGRP) (11,13), whereas the other population expresses anorexigenic proopiomelanocortin (POMC) and cocaine-and amphetamine-regulated transcript (CART) (14). Both these groups undergo degeneration in the anorexic anx/anx mouse (15). By P21, anx/anx mice exhibit fewer hypothalamic fibers immunoreactive (ir) for AGRP and NPY (7,8,10,11,16), as well as α-melanocyte-stimulating hormone (αMSH) and CART (7,9).…”

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confidence: 99%

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Hypothalamic mitochondrial dysfunction associated with anorexia in the anx/anx mouse

Lindfors

Nilsson

García-Rovés

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The anorectic anx/anx mouse exhibits disturbed feeding behavior and aberrances, including neurodegeneration, in peptidergic neurons in the appetite regulating hypothalamic arcuate nucleus. Poor feeding in infants, as well as neurodegeneration, are common phenotypes in human disorders caused by dysfunction of the mitochondrial oxidative phosphorylation system (OXPHOS). We therefore hypothesized that the anorexia and degenerative phenotypes in the anx/anx mouse could be related to defects in the OXPHOS. In this study, we found reduced efficiency of hypothalamic OXPHOS complex I assembly and activity in the anx/anx mouse. We also recorded signs of increased oxidative stress in anx/anx hypothalamus, possibly as an effect of the decreased hypothalamic levels of fully assembled complex I, that were demonstrated by native Western blots. Furthermore, the Ndufaf1 gene, encoding a complex I assembly factor, was genetically mapped to the anx interval and found to be down-regulated in anx/ anx mice. These results suggest that the anorexia and hypothalamic neurodegeneration of the anx/anx mouse are associated with dysfunction of mitochondrial complex I.neuropeptides | reactive oxygen species | agouti-gene related protein | food intake | neuroinflammation T he anorectic anx/anx mouse (1) is an attractive model for disturbed feeding behavior, as it exhibits phenotypes associated with failure to thrive in infants and young children (2), anorexia nervosa (3), and cachexia (4). This mouse arose by a spontaneous mutation (anorexia, allele symbol anx) and is characterized by poor appetite and reduced stomach content, and dies (likely because of the severe starvation) around 3 wk after birth (1). The anx/ anx mice eat significantly less than their wild-type littermates, and by postnatal day (P) 21 they weigh half as much, rendering them an emaciated appearance (1). These mice also exhibit a number of neurological abnormalities, such as body tremors, head weaving, hyperactivity, and uncoordinated gait (1).Several neurotransmitter (5, 6) and neuropeptidergic (7-11) systems involved in the regulation of food intake and energy metabolism are disturbed in the anx/anx mouse. The majority of these findings are centered around the hypothalamus, the origin of a neuronal network important for the control of initiation and termination of food intake, as well as diet-induced thermogenesis and energy expenditure. The arcuate nucleus of hypothalamus (Arc), situated at the interface between the periphery and brain, receives signals about energy status from the periphery, such as circulating leptin and insulin levels, resulting in anorexigenic or orexigenic behavior. Two main populations of food intake-regulating neurons reside in the Arc, both expressing leptin and insulin receptors (12). One group coexpresses the two orexigenic neuropeptides neuropeptide Y (NPY) and agoutigene related protein (AGRP) (11, 13), whereas the other population expresses anorexigenic proopiomelanocortin (POMC) and cocaine-and amphetamine-regulated transcript (CART) (14)...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 57%

mentioning

confidence: 52%

mentioning

confidence: 99%

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Hypothalamic mitochondrial dysfunction associated with anorexia in the anx/anx mouse

Lindfors

Nilsson

García-Rovés

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, studies have demonstrated inflammation in the hypothalamus of the anx/anx mouse (26,35,37). Taken together, these observations provide an explanation for the hypothalamic dysfunction and neurodegeneration found in anx mutant mice (38).…”

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confidence: 50%

Glucose intolerance and pancreatic β-cell dysfunction in the anorecticanx/anxmouse

Lindfors

Katz

Selander

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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mation and impaired mitochondrial oxidative phosphorylation are considered key players in the development of several metabolic disorders, including diabetes. We have previously shown inflammation and mitochondrial dysfunction in the hypothalamus of an animal model for anorexia, the anx/anx mouse. Moreover, increased incidence of eating disorders, e.g., anorexia nervosa, has been observed in diabetic individuals. In the present investigation we evaluated whether impaired mitochondrial phosphorylation and inflammation also occur in endocrine pancreas of anorectic mice, and if glucose homeostasis is disturbed. We show that anx/anx mice exhibit marked glucose intolerance associated with reduced insulin release following an intraperitoneal injection of glucose. In contrast, insulin release from isolated anx/anx islets is increased after stimulation with glucose or KCl. In isolated anx/anx islets there is a strong downregulation of the mitochondrial complex I (CI) assembly factor, NADH dehydrogenase (ubiquinone) 1␣ subcomplex, assembly factor 1 (Ndufaf1), and a reduced CI activity. In addition, we show elevated concentrations of free fatty acids (FFAs) in anx/anx serum and increased macrophage infiltration (indicative of inflammation) in anx/anx islets. However, isolated islets from anx/anx mice cultured in the absence of FFAs do not exhibit increased inflammation. We conclude that the phenotype of the endocrine pancreas of the anx/anx mouse is characterized by increased levels of circulating FFAs, as well as inflammation, which can inhibit insulin secretion in vivo. The anx/anx mouse may represent a useful tool for studying molecular mechanisms underlying the association between diabetes and eating disorders.anorexia; free fatty acids; insulin; macrophages; mitochondrial dysfunction THERE IS INCREASING EVIDENCE that inflammation in animals and humans is important for the development of several metabolic disorders, including diabetes (2,8,9,46,47,49). Animal studies show that inflammation induced by obesity following high-fat diet is associated with insulin and leptin resistance, lost control of energy expenditure, macrophage infiltration, and pancreatic islet dysfunction (2, 21, 49).The anorectic anx/anx mouse arose by a spontaneous mutation in 1976. These mice develop self-starvation and emaciation and die at about 3 wk of age (32). They eat approximately half as much as the normal littermates (32). Thus the anx/anx mouse is an attractive model for studying regulation of feeding behavior, in particular anorexia, due to the development of core features associated with human conditions such as anorexia nervosa (AN) (24) and failure to thrive (23). The anx/anx mouse exhibits several alterations in hypothalamic neurotransmitter/peptide circuits involved in regulation of food intake (4 -6, 12, 20, 37, 38). Moreover, the anx mutation is linked to downregulation of the NADH dehydrogenase (ubiquinone) 1␣ subcomplex, assembly factor 1 (Ndufaf1), involved in the assembly of complex I (CI) in the mitochondrial oxidative phosph...

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Epigenetic regulation of the cannabinoid receptor CB1 in an activity‐based rat model of anorexia nervosa

D’Addario

Zaplatić

Giunti

et al. 2020

Intl J Eating Disorders

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Objective: Both environmental and genetic factors are known to contribute to the development of anorexia nervosa (AN), but the exact etiology remains poorly understood. Herein, we studied the transcriptional regulation of the endocannabinoid system, an interesting target for body weight maintenance and the control of food intake and energy balance.Method: We used two well-characterized animal models of AN: (a) the activity-based anorexia (ABA) model in which rats, housed with running wheels and subjected to daily food restriction, show reductions in body weight and increase in physical activity; (b) the genetic anx/anx mouse displaying the core features of AN: low food intake and emaciation.Results: Among the evaluated endocannabinoid system components, we observed a selective and significant down-regulation of the gene encoding for the type 1 cannabinoid receptor (Cnr1) in ABA rats' hypothalamus and nucleus accumbens and, in the latter area, a consistent, significant and correlated increase in DNA methylation at the gene promoter. No changes were evident in the anx/anx mice except for a downregulation of Cnr1, in the prefrontal cortex.Discussion: Our findings support a possible role for Cnr1 in the ABA animal model of AN. In particular, its regulation in the nucleus accumbens appears to be triggered by environmental cues due to the consistent epigenetic modulation of the promoter.These data warrant further studies on Cnr1 regulation as a possible target for treatment of AN.

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Evidence of hypothalamic degeneration in the anorectic anx/anx mouse

Cited by 25 publications

References 62 publications

Hypothalamic mitochondrial dysfunction associated with anorexia in the anx/anx mouse

Hypothalamic mitochondrial dysfunction associated with anorexia in the anx/anx mouse

Glucose intolerance and pancreatic β-cell dysfunction in the anorecticanx/anxmouse

Epigenetic regulation of the cannabinoid receptor CB1 in an activity‐based rat model of anorexia nervosa

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