Aberrant agouti‐related protein system in the hypothalamus of the <i>anx/anx</i> mouse is associated with activation of microglia

Nilsson, Ida; Lindfors, Charlotte; Fetissov, Sergueı̈ O.; Hökfelt, Tomas; Johansen, Jeanette E.

doi:10.1002/cne.21599

Cited by 42 publications

(38 citation statements)

References 88 publications

(117 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

“…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).…”

supporting

confidence: 51%

“…There are a number of possible explanations for the anorectic phenotype in the anx/anx mouse (1) as well as for the aberrant appearance and degeneration of the arcuate food intake-regulating circuitries in this mouse (5,(7)(8)(9)(10)16). Here we provide evidence for mitochondrial dysfunction in the hypothalamus of the anx/anx mouse.…”

Section: Discussionmentioning

confidence: 99%

“…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). 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.…”

mentioning

confidence: 99%

See 3 more Smart Citations

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.

Self Cite

View full text Add to dashboard Cite

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)...

show abstract

Section: Discussionsupporting

confidence: 93%

supporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our findings echo the results of Lachuer et al (44), who found differential expression of several genes cytokines in anx/anx mice hypothalamus, and a recent neuropathological study that found activated microglia in several brain regions, supporting a CNS inflammation/neurodegeneration-associated process (54). Although the underlying mechanisms are unknown, glia can be activated after injury, releasing chemical mediators such as CNS cytokines.…”

Section: Hypothalamus Transcriptome Reveals Cachexia In Anx/anxsupporting

confidence: 91%

Hypothalamus transcriptome profile suggests an anorexia-cachexia syndrome in the anx/anx mouse model

Mercader

Lozano

Sumoy

et al. 2008

Physiological Genomics

View full text Add to dashboard Cite

Mercader JM, Lozano JJ, Sumoy L, Dierssen M, Visa J, Gratacòs M, Estivill X. Hypothalamus transcriptome profile suggests an anorexia-cachexia syndrome in the anx/anx mouse model. Physiol Genomics 35: 341-350, 2008. First published September 23, 2008 doi:10.1152/physiolgenomics.90255.2008The anx/anx mouse displays poor appetite and lean appearance and is considered a good model for the study of anorexia nervosa. To identify new genes involved in feeding behavior and body weight regulation we performed an expression profiling in the hypothalamus of the anx/anx mice. Using commercial microarrays we detected 156 differentially expressed genes and validated 92 of those using TaqMan low-density arrays. The expression of a set of 87 candidate genes selected based on literature evidences was also quantified by TaqMan low-density arrays. Our results showed enrichment in deregulated genes involved in cell death, cell morphology, and cancer, as well as an alteration of several signaling circuits involved in energy balance including neuropeptide Y and melanocortin signaling. The expression profile along with the phenotype led us to conclude that anx/anx mice resemble the anorexia-cachexia syndrome typically observed in cancer, infection with human immunodeficiency virus or chronic diseases, rather than starvation, and that anx/anx mice could be considered a good model for the treatment and investigation of this condition. feeding regulation; chronic disorders; gene expression; TaqMan lowdensity arrays; microarrays ENERGY BALANCE AND BODY WEIGHT regulation are major homeostatic processes, and the disruption of their regulatory mechanisms can cause several complications, leading to death in the worst cases. In humans, deregulation of these mechanisms occurs in patients with eating disorders (ED), such as anorexia nervosa (AN) and bulimia nervosa (BN), and obesity. ED and obesity, major health problems in adolescents, are associated with elevated risk for a broad range of physical and mental disorders during early adulthood (1, 6, 69). In developed countries, the incidence of AN or BN has dramatically increased in recent years (39), though other diseases such as cancer or chronic infections can be also associated with an energy balance impairment characterized by progressive weight loss and depletion of adipose and skeletal muscle reserves, known as cachexia, which can aggravate the outcome of the disease (73). In these cases, anorexia appears in response to acute and chronic infections, inflammation, and trauma, followed by severe loss of body weight due to a deregulation of the appetite-regulating hypothalamic circuitry.One animal model proposed for the study of anorexia is the anx/anx mouse, a mutant that harbors a recessive mutation in chromosome 2, not yet identified, close to the Pallidin gene (36, 49). These mice display poor appetite resulting in growth failure and emaciated appearance, accompanied by abnormal behavior and neurological symptoms including body tremors, head weaving, hyperactivity, and uncoordinated gat...

show abstract

Early microglia activation in a mouse model of chronic glaucoma

Bosco¹,

Steele²,

Vetter³

2011

J of Comparative Neurology

296

218

View full text Add to dashboard Cite

Changes in microglial cell activation and distribution are associated with neuronal decline in the CNS, particularly under pathological conditions. Activated microglia converge on the initial site of axonal degeneration in human glaucoma, yet, their part in its pathophysiology remains unresolved. To begin with, it is unknown whether microglia activation precedes or is a late consequence of retinal ganglion cell (RGC) neurodegeneration. Here, we address this critical element in DBA/2J (D2) mice, an established model of chronic inherited glaucoma, using as a control the congenic substrain DBA/2J Gpnmb+/SjJ (D2G), which is not affected by glaucoma. We analyzed the spatial distribution and timecourse of microglial changes in the retina, as well as within the proximal optic nerve prior to and throughout ages when neurodegeneration has been reported. Exclusively in D2 mice, we detected early microglia clustering in the inner central retina and unmyelinated optic nerve regions, with microglia activation peaking by 3 months of age. Between 5 and 8 months of age, activated microglia persisted and concentrated in the optic disc, but also localized to the retinal periphery. Collectively, our findings suggest microglia activation is an early alteration in the retina and optic nerve in D2 glaucoma, potentially contributing to disease onset or progression. Ultimately, detection of microglial activation may have value in early disease diagnosis, while modulation of microglial responses may alter disease progression.

show abstract

Aberrant agouti‐related protein system in the hypothalamus of the anx/anx mouse is associated with activation of microglia

Cited by 42 publications

References 88 publications

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

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

Hypothalamus transcriptome profile suggests an anorexia-cachexia syndrome in the anx/anx mouse model

Early microglia activation in a mouse model of chronic glaucoma

Contact Info

Product

Resources

About