No abstract

Objective The increasing prevalence of obesity makes it important to increase the understanding of the maturation and function of the neuronal integrators and regulators of metabolic function. Methods Behavioral, molecular, and physiological analyses of transgenic mice with Sine oculis 3 ( Six3 ) deleted in mature neurons using the Synapsin cre allele. Results Conditional deletion of the homeodomain transcription factor Six3 in mature neurons causes dwarfism and weakens circadian wheel-running activity rhythms but increases general activity at night, and improves metabolic function, without impacting pubertal onset or fertility in males. The reduced growth in 6-week-old Six3 fl/fl :Synapsin cre ( Six3 syn ) males correlates with increased somatostatin (SS) expression in the hypothalamus and reduced growth hormone (GH) in the pituitary. In contrast, 12-week-old Six3 syn males have increased GH release, despite an increased number of the inhibitory SS neurons in the periventricular nucleus. GH is important in glucose metabolism, muscle function, and bone health. Interestingly, Six3 syn males have improved glucose tolerance at 7, 12, and 18 weeks of age, which, in adulthood, is associated with increased % lean mass and increased metabolic rates. Further, 12-week-old Six3 syn males have reduced bone mineralization and a lower bone mineral density, indicating that reduced GH levels during early life cause a long-term reduction in bone mineralization. Conclusion Our study points to the novel role of Six3 in post-proliferative neurons to regulate metabolic function through SS neuron control of GH release.

No abstract

Skin lesions associated with alpha 1-antitrypsin deficiency are becoming better defined and understood. Deficiency in this major antiproteinase, which neutralizes multiple proteolytic enzymes ranging from collagenases and elastases to trypsin and chymotrypsin, thus results in significant tissue autodigestion. This anti-proteinase is secreted by activated lymphocytes and macrophages, suggesting the existence of homeostasis which titrates the release of proteolytic enzymes by these cells, and the adequate neutralization of these proteases in order to prevent excessive tissue autodigestion each time these inflammatory cells are activated. We report a patient with alpha 1-antitrypsin deficiency who, following insect bites and cellulitis developed widespread itching and scratching, leading to widespread lesions of prurigo nodularis. The colonization of his multiple skin lesions with Staphylococcus aureus and the release of potent T cell mitogens, such as Protein A and enterotoxin A from the bacterial cell membrane may have resulted in the release of additional proteolytic enzymes by the activated lymphocytes and macrophages, without the concomitant secretion of alpha 1-antitrypsin with subsequent aggravation of his pruritus. These concepts are supported by electron microscopic evidence of excessive tissue autodigestion, and by immunocytochemical data identifying the presence of T helper and T cytotoxic/suppressor lymphocytes as well as macrophages within the upper dermis.