Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control.

We describe a protocol for the rapid and sensitive quantification of disease severity in mouse models of cerebella ataxia. It is derived from previously published phenotype assessments in several disease models, including spinocerebellar ataxias, Huntington s disease and spinobulbar muscular atrophy. Measures include hind limb clasping, ledge test, gait and kyphosis. Each measure is recorded on a scale of 0-3, with a combined total of 0-12 for all four measures. The results effectively discriminate between affected and non-affected individuals, while also quantifying the temporal progression of neurodegenerative disease phenotypes. Measures may be analyzed individually or combined into a composite phenotype score for greater statistical power. The ideal combination of the four described measures will depend upon the disorder in question. We present an example of the protocol used to assess disease severity in a transgenic mouse model of spinocerebellar ataxia type 7 (SCA7).Albert R. La Spada and Gwenn A. Garden contributed to this manuscript equally. ProtocolTo prevent bias, the experimenter performing the assessments should not have knowledge of the animal's genotype. Individual measures are scored on a scale of 0-3, with 0 representing an absence of the relevant phenotype and 3 representing the most severe manifestation. Each test is performed multiple times to ensure that the score is reproducible. Obesity will complicate the interpretation of all measures described. The investigator may wish to weigh mice following phenotype scoring to assess the possible role of adiposity in the results. Ledge testThe ledge test is a direct measure of coordination, which is impaired in cerebellar ataxias and many other neurodegenerative disorders. This measure is the most directly comparable to human signs of cerebellar ataxia. Hindlimb claspingHindlimb clasping is a marker of disease progression in a number of mouse models of neurodegeneration, including certain cerebellar ataxias [1]. GaitGait is a measure of coordination and muscle function. Page 1 of 3Journal of Visualized Experiments www.jove.comCopyright © 2010 Journal of Visualized Experiments 1. Lift the mouse from the cage and place it on the cage's ledge. Mice will typically walk along the ledge and attempt to descend back into the cage. 2. Observe the mouse as it walks along the cage ledge and lowers itself into its cage. A wild-type mouse will typically walk along the ledge without losing its balance, and will lower itself back into the cage gracefully, using its paws. This is assigned a score of 0. If the mouse loses its footing while walking along the ledge, but otherwise appears coordinated, it receives a score of 1. If it does not effectively use its hind legs, or lands on its head rather than its paws when descending into the cage, it receives a score of 2. If it falls off the ledge, or nearly so, while walking or attempting to lower itself, or shakes and refuses to move at all despite encouragement, it receives a score of 3. Some mice will require ...

The observational evidence does not support the hypothesis that dairy fat or high-fat dairy foods contribute to obesity or cardiometabolic risk, and suggests that high-fat dairy consumption within typical dietary patterns is inversely associated with obesity risk. Although not conclusive, these findings may provide a rationale for future research into the bioactive properties of dairy fat and the impact of bovine feeding practices on the health effects of dairy fat.

Non-neuronal cells may be pivotal in neurodegenerative disease, but the mechanistic basis of this effect remains ill-defined. In the polyglutamine disease spinocerebellar ataxia type 7 (SCA7), Purkinje cells undergo non-cell-autonomous degeneration in transgenic mice. We considered the possibility that glial dysfunction leads to Purkinje cell degeneration, and generated mice that express ataxin-7 in Bergmann glia of the cerebellum with the Gfa2 promoter. Bergmann glia-specific expression of mutant ataxin-7 was sufficient to produce ataxia and neurodegeneration. Expression of the Bergmann glia-specific glutamate transporter GLAST was reduced in Gfa2-SCA7 mice and was associated with impaired glutamate transport in cultured Bergmann glia, cerebellar slices and cerebellar synaptosomes. Ultrastructural analysis of Purkinje cells revealed findings of dark cell degeneration consistent with excitotoxic injury. Our studies indicate that impairment of glutamate transport secondary to glial dysfunction contributes to SCA7 neurodegeneration, and suggest a similar role for glial dysfunction in other polyglutamine diseases and SCAs.