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alpha-Melanocyte stimulating hormone (alpha-MSH) is known to be the main physiologic regulator for integumental pigmentation of various vertebrate species. However, the role of alpha-MSH and related melanocortins in the regulation of human cutaneous pigmentation is only beginning to be understood. Cloning of the melanocortin-1 receptor (MC1R), and the feasibility of establishing normal human epidermal melanocyte cultures have made it possible to demonstrate direct and specific biological effects of alpha-MSH on these cells. It is now recognized that both alpha-MSH and ACTH have similar mitogenic and melanogenic effects on human epidermal melanocytes. These effects are mediated by binding of these hormones to the specific MC1R that recognizes them both with similar affinity. Human MC1R is homologous to its mouse counterpart in that its activation leads to stimulation of eumelanin synthesis. MC1R is also the binding site for agouti signaling protein (ASP), the product of the agouti locus. Human epidermal melanocytes respond to purified recombinant mouse or human ASP, with a reduction in basal tyrosinase activity, and complete abrogation of the mitogenic and melanogenic effects of alpha-MSH. These results suggest that ASP induces pheomelanin synthesis by competing with alpha-MSH for binding to the MC1R. This receptor seems to be subject to regulation by a variety of paracrine and/or autocrine factors that are synthesized in response to exposure of the skin to ultraviolet radiation (UVR). Activation of MC1R seems to be pivotal for UV-induced melanogenesis, since stimulation of the cAMP pathway plays a key role in the melanogenic response of human epidermal melanocytes. The melanogenic response to UVR might be influenced by the presence of allelic variants of the MC1R gene. Allelic variants have been identified and shown to be associated with red hair, poor tanning ability, and possibly melanoma. The possible influence of these variants on the function of the MC1R needs to be investigated, in order to understand the physiological consequence of these mutations. Also, the interaction of alpha-MSH with other factors that are known to affect pigmentation needs to be better understood in order to define the role possible of this hormone and its receptor in acquired human cutaneous hyper- or hypopigmentation.

BACKGROUND: The Agouti-related protein (AGRP), an appetite modulator, induces hyperphagia when administered intracerebroventricularly or when overexpressed in transgenic mice. Exogenous administration of AGRP in rodents predisposes to high fat and high sugar intakes. OBJECTIVE: The objective was to examine the potential associations of 2 ethnic-specific polymorphisms in the AGRP gene (Ala67Thr in whites and -38C>T in blacks) in the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study. DESIGN: We examined the effect of the 2 polymorphisms in the AGRP gene on self-reported macronutrient intakes in 478 white and 272 black participants in the HERITAGE Family Study. RESULTS: Both AGRP polymorphisms showed a significant association with energy intake. In whites, a smaller proportion of total energy was derived from fat by the Ala67Thr heterozygotes ([Formula: see text] ± SEM: 29.4 ± 0.7%) than by the Ala67Ala homozygotes (31.5 ± 0.5%; P = 0.009), mainly because of a lower intake of saturated (P = 0.06) and monounsaturated (P = 0.01) fats by the Ala67Thr heterozygotes. The percentage of energy from carbohydrates was 2.6% greater in the Ala67Thr heterozygotes (55.1 ± 1.1%) than in the Ala67Ala homozygotes (52.5 ± 0.6%; P = 0.03). In blacks, protein intake was associated with the -38C>T promoter polymorphism. T/T homozygotes had a significantly lower protein intake than did the C-allele carriers (C/C: 16.8 ± 0.4%; C/T: 17.2 ± 0.2%; T/T: 15.4 ± 0.7%; P = 0.04). No significant differences in total energy and alcohol intakes existed between genotype groups in blacks or whites. CONCLUSIONS: The present study suggests that 2 ethnic-specific AGRP variants, previously shown to be associated with leanness in the HERITAGE Family Study, are also associated with macronutrient intake.

The human homologues of recently discovered murine obesity genes provide relevant candidates to study the genetic component of obesity in humans. We analysed the human counterparts to murine obesity genes ob, db, agouti, tub, melanocortin 4-receptor (MC4-R) and mitochondrial uncoupling proteins 2 and 3 (UCP2 and UCP3), as well as two other chromosomal regions reported to be linked to obesity-related phenotypes in restricted populations. We found no significant evidence for linkage to any analysed loci in our total study material of 105 affected sib pairs collected from the genetically homogenous population of Finland. However, several markers on 14 cM chromosomal region flanking the MC4-R gene showed sharing of alleles identical-by-descent (IBD) more frequently than expected. A selected subset of non-diabetic obese sib pairs strengthened the P values down to 0.003 in this particular region. The smallest P value (P = 0.001) was obtained with a marker D18S487 in a subgroup containing only sib pairs with one lean and one obese parent. We therefore screened seven obese subjects included in our sib pair material for sequence changes in their MC4-R gene, but no mutations of apparent causal relationship were found. In conclusion, we could not find evidence for significant contribution of the chromosomal loci corresponding to the murine single gene obesity genes for human morbid obesity, but additional studies are still needed to clarify whether DNA alterations within or adjacent to the MC4-R gene play some role.

Mutations of the mouse Attractin (Atrn; formerly mahogany) gene were originally recognized because they suppress Agouti pigment type switching. More recently, effects independent of Agouti have been recognized: mice homozygous for the Atrnmg-3J allele are resistant to diet-induced obesity and also develop abnormal myelination and vacuolation in the central nervous system. To better understand the pathophysiology and relationship of these pleiotropic effects, we further characterized the molecular abnormalities responsible for two additional Atrn alleles, Atrnmg and Atrnmg-L, and examined in parallel the phenotypes of homozygous and compound heterozygous animals. We find that the three alleles have similar effects on pigmentation and neurodegeneration, with a relative severity of Atrnmg-3J > Atrnmg > Atrnmg-L, which also corresponds to the effects of the three alleles on levels of normal Atrn mRNA. Animals homozygous for Atrnmg-3J or Atrnmg, but not Atrnmg-L, show reduced body weight, reduced adiposity, and increased locomotor activity, all in the presence of normal food intake. These results confirm that the mechanism responsible for the neuropathological alteration is a loss—rather than gain—of function, indicate that abnormal body weight in Atrn mutant mice is caused by a central process leading to increased energy expenditure, and demonstrate that pigmentation is more sensitive to levels of Atrn mRNA than are nonpigmentary phenotypes.

There is increasing evidence that epigenetic information can be inherited across generations in mammals, despite extensive reprogramming both in the gametes and in the early developing embryo. One corollary to this is that disrupting the establishment of epigenetic state in the gametes of a parent, as a result of heterozygosity for mutations in genes involved in reprogramming, could affect the phenotype of offspring that do not inherit the mutant allele. Here we show that such effects do occur following paternal inheritance in the mouse. We detected changes to transcription and chromosome ploidy in adult animals. Paternal effects of this type have not been reported previously in mammals and suggest that the untransmitted genotype of male parents can influence the phenotype of their offspring.

Background Metal ions are important micronutrients in cellular metabolism, but excess ions that cause toxic reactive oxygen species are harmful to cells. In bacteria, Fur family proteins such as Fur, Zur and PerR manage the iron and zinc uptake and oxidative stress responses, respectively. The single Fur-like protein (annotated as PerR) in Streptococcus suis has been demonstrated to be involved in zinc and iron uptake in previous studies, but the reports on oxidative stress response and gene regulation are limited. Results In the present study, the perR gene deletion mutant ΔperR was constructed in Streptococcus suis serotype 2 strain SC-19, and the mutant strain ΔperR exhibited less sensitivity to H2O2 stress compared to the wild-type. The dpr and metQIN were found to be upregulated in the ΔperR strain compared with SC-19. Electrophoretic mobility shift assays showed that the promoters of dpr and metQIN could be bound by the PerR protein. These results suggest that dpr and metQIN are members of the PerR regulon of S. suis. dpr encodes a Dps-like peroxide resistance protein, and the dpr knockout strains (Δdpr and ΔdprΔperR) were highly sensitive to H2O2. MetQIN is a methionine transporter, and the increased utilization of methionine in the ΔperR strain indirectly affected the peroxide resistance. Using a promoter–EGFP gene fusion reporting system, we found that the PerR regulon was induced by H2O2, and the induction was modulated by metal ions. Finally, we found that the pathogenicity of the perR mutant was attenuated and easily cleared by mice. Conclusions These data strongly suggest that the Fur-like protein PerR directly regulates dpr and metQIN and plays a crucial role in oxidative stress response in S. suis.