Sex Dimorphic Changes in Trh Gene Methylation and Thyroid-Axis Response to Energy Demands in Maternally Separated Rats.

The hypothalamus-pituitary-thyroid (HPT) axis regulates energy balance through the pleiotropic action of thyroid hormones. HPT basal activity and stimulation by cold or voluntary exercise are repressed by previous chronic stress in adults. Maternal separation (MS) modifies HPT basal activity; we thus studied the response of the axis to energy demands and analyzed possible epigenetic changes on Trh promoter. Nonhandled (NH) or MS male Wistar rats were cold exposed 1 h at adulthood; Trh expression in the hypothalamic paraventricular nucleus (PVN) and serum thyrotropin (TSH) concentration were increased only in NH rats. Two weeks of voluntary exercise decreased fat mass and increased Trh expression, and thyroid hormones concentration changed proportionally to running distance in NH male rats and MS male rats. Although NH females ran more than MS and much more than males, exercise decreased body weight and fat mass only in NH rats with no change on any parameter of the HPT axis but increased Pomc expression in arcuate-nucleus of NH and Npy in MS females. Overall, the methylation pattern of PVN Trh gene promoter was similar in NH males and females; MS modified methylation of specific CpG sites, a thyroid hormone receptor (THR)-binding site present after the initiation site was hypomethylated in MS males; in MS females, the THR binding site of the proximal promoter (site 4) and 2 sites in the first intron were hypermethylated. Our studies showed that, in a sex-dimorphic manner, MS blunted the responses of HPT axis to energy demands in adult animals and caused methylation changes on Trh promoter that could alter T3 feedback.

Neonatal Maternal Separation Alters, in a Sex-Specific Manner, the Expression of TRH, of TRH-Degrading Ectoenzyme in the Rat Hypothalamus, and the Response of the Thyroid Axis to Starvation.

Hypothalamic-pituitary-thyroid (HPT) axis activity is important for energy homeostasis, and is modified by stress. Maternal separation (MS) alters the stress response and predisposes to metabolic disturbances in the adult. We therefore studied the effect of MS on adult HPT axis activity. Wistar male and female pups were separated from their mothers 3 h/d during postnatal day (PND)2-PND21 (MS), or left nonhandled (NH). Open field and elevated plus maze tests revealed increased locomotion in MS males and anxiety-like behavior in MS females. At PND90, MS females had increased body weight gain, Trh expression in the hypothalamic paraventricular nucleus, and white adipose tissue mass. MS males had increased expression of TRH-degrading enzyme in tanycytes, reduced TSH and T3, and enhanced corticosterone serum concentrations. MS stimulated brown adipose tissue deiodinase 2 activity in either sex. Forty-eight hours of fasting (PND60) augmented serum corticosterone levels similarly in MS or NH females but more in MS than in NH male rats. MS reduced the fasting-induced drop in hypothalamic paraventricular nucleus-Trh expression of males but not of females and abolished the fasting-induced increase in Trh expression in both sexes. Fasting reduced serum concentrations of TSH, T4, and T3, less in MS than in NH males, whereas in females, TSH decreased in MS but not in NH rats, but T4 and T3 decreased similarly in NH and MS rats. In conclusion, MS produced long-term changes in the activity of the HPT axis that were sex specific; response to fasting was partially blunted in males, which could affect their adaptive response to negative energy balance.

Creb and Sp/Krüppel response elements cooperate to control rat TRH gene transcription in response to cAMP.

Expression of hypophysiotropic TRH, that controls thyroid axis activity, is increased by cold exposure; this effect is mimicked in rat hypothalamic cells incubated with norepinephrine or cAMP analogs. TRH proximal promoter contains three putative CRE: Site-4 or CRE-1 that overlaps an element recognized by thyroid hormone receptors, CRE-2 with adjacent sequences GC box or CACCC recognized by Sp/Krüppel factors (extended CRE-2), and AP-1 sites flanking a GRE(1/2). To evaluate the role of each element in the cAMP response, these sites were mutated or deleted in rat TRH promoter linked to luciferase gene (TRH-luc) and co-transfected with ß-gal expression vector in various cell lines; C6 cells gave the highest response to forskolin. Basal activity was most affected by mutations or deletion of CRE-2 site, or CACCC (50-75% of wild type-WT). Forskolin-induced 3× stimulation in WT which decreased 25% with CRE-1 or AP-1 deletions, but 50% when CRE-2 or its 5' adjacent GC box was altered. SH-SY5Y cells co-transfected with CREB-expression vector increased dB-cAMP response in the wild type but not in the CRE-2 mutated plasmid; cotransfecting CREB-A (a dominant negative expression vector) strongly diminished basal or cAMP response. Primary cultures of hypothalamic cells transfected with plasmids containing deletions of CRE-1, CRE-2, or extended CRE-2 failed to respond to forskolin when CRE-2 was modified. These results corroborate the CRE-2 site as the main cAMP-response element of rat TRH promoter, not exclusive of transcription factors of hypothalamic cells, and stress the relevance of adjacent Sp-1 sites, important mediators of some metabolic hormones.

The 1,450-nm diode laser reduces sebum production in facial skin: a possible mode of action of its effectiveness for the treatment of acne vulgaris.

BACKGROUND AND OBJECTIVES: Over the last several years, several light-based systems have been employed for the treatment of acne vulgaris. The 1,450-nm diode laser has been shown to improve acne, and this has been suggested to be due to effects on sebaceous glands. However, an effect on sebum production has not been demonstrated. The objective of this study was to evaluate if the 1,450-nm diode laser indeed reduces sebum production. STUDY DESIGN/MATERIALS AND METHODS: Eight patients with a history of acne were recruited and treated with the 1,450-nm diode laser on the right side of the nose over a 6-week period, for a total of three treatments. Sebum production was quantified using the Sebutape method. RESULTS: The number of sebum-producing follicles was reduced by 8.5 and 16.7% at weeks 4 and 6, respectively (P<0.05). A significant reduction in total collected sebum (-18%) was observed at week 6. CONCLUSION: This data suggests that the clinical effectiveness of the 1,450-nm diode laser may be based, at least in part, on its effects on sebaceous glands, with subsequent reduction in sebum production.

Metabolic diseases and pregnancy.

The skin mirrors the hormonal metabolic and physiologic changes that occur during pregnancy. The metabolic effects are manifested primarily in accentuation of two disorders, porphyria cutanea tarda and acrodermatitis enteropathica. The former may be exacerbated, not only during pregnancy, but also during the post-partum period and with the intake of estrogen-containing birth control pills. Exacerbations of acrodermatitis enteropathica characteristically appear during pregnancy.