The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.

In the periphery, the nutrient-sensing enzyme Sirtuin 1 (silent mating type information regulation 2 homolog 1 [Sirt1]) reduces body weight in diet-induced obese (DIO) rodents. However, the role of hypothalamic Sirt1 in body weight and energy balance regulation is debated. The first studies to reveal that central Sirt1 regulates body weight came from experiments in our laboratory using Sprague-Dawley rats. Central inhibition of Sirt1 decreased body weight and food intake as a result of a forkhead box protein O1 (FoxO1)-mediated increase in the anorexigenic proopiomelanocortin (POMC) and decrease in the orexigenic Agouti-related peptide in the hypothalamic arcuate nucleus. Here, we demonstrate that central inhibition of Sirt1 in DIO decreased body weight and increased energy expenditure at higher levels as compared with the lean counterpart. Brain Sirt1 inhibition in DIO increased acetylated FoxO1, which in turn increased phosphorylated FoxO1 via improved insulin/phosphorylated AKT signaling. Elevated acetylated FoxO1 and phosphorylated FoxO1 increased POMC along with the α-melanocyte-stimulating hormone (α-MSH) maturation enzyme carboxypeptidase E, which resulted in more of the bioactive POMC product α-MSH released into the paraventricular nucleus. Increased in α-MSH led to augmented TRH levels and circulating T3 levels (triiodothyronine, thyroid hormone). These results indicate that inhibiting hypothalamic Sirt1 in DIO enhances the activity of the hypothalamic-pituitary-thyroid axis, which stimulates energy expenditure. Because we show that blocking central Sirt1 causes physiological changes that promote a negative energy balance in an obese individual, our results support brain Sirt1 as a significant target for weight loss therapeutics.

Cyr NE, Toorie AM, Steger JS, Sochat MM, Hyner S, Perello M, Stuart R, Nillni EA. Mechanisms by which the orexigen NPY regulates anorexigenic ␣-MSH and TRH. Am J Physiol Endocrinol Metab 67: E640 -E650, 2013. First published January 15, 2013; doi:10.1152/ajpendo.00448.2012.-Protein posttranslational processing is a cellular mechanism fundamental to the generation of bioactive peptides, including the anorectic ␣-melanocyte-stimulating hormone (␣-MSH) and thyrotropin-releasing hormone (TRH) peptides produced in the hypothalamic arcuate (ARC) and paraventricular (PVN) nuclei, respectively. Neuropeptide Y (NPY) promotes positive energy balance in part by suppressing ␣-MSH and TRH. The mechanism by which NPY regulates ␣-MSH output, however, is not well understood. Our results reveal that NPY inhibited the posttranslational processing of ␣-MSH's inactive precursor proopiomelanocortin (POMC) by decreasing the prohormone convertase-2 (PC2). We also found that early growth response protein-1 (Egr-1) and NPY-Y1 receptors mediated the NPY-induced decrease in PC2. NPY given intra-PVN also decreased PC2 in PVN samples, suggesting a reduction in PC2-mediated pro-TRH processing. In addition, NPY attenuated the ␣-MSH-induced increase in TRH production by two mechanisms. First, NPY decreased ␣-MSH-induced CREB phosphorylation, which normally enhances TRH transcription. Second, NPY decreased the amount of ␣-MSH in the PVN. Collectively, these results underscore the significance of the interaction between NPY and ␣-MSH in the central regulation of energy balance and indicate that posttranslational processing is a mechanism that plays a specific role in this interaction.␣-melanocyte-stimulating hormone; early growth response protein-1; neuropeptide Y; proopiomelanocortin; thyrotropin-releasing hormone OBESITY IS A MAJOR HEALTH and socioeconomic concern that has reached epidemic proportions in developed nations. Despite efforts to abate the problem, cases of obesity continue to rise. Thus, it is imperative to better understand the physiological mechanisms controlling food intake and body weight.Neuropeptide Y (NPY) is a potent orexigen that has received attention as an antiobesity drug target (69). NPY is produced both centrally and peripherally. Although it is widely distributed throughout the brain, in situ hybridization studies reveal that NPY is most densely localized to the hypothalamic arcuate nucleus (ARC) (19,41). Hypothalamic NPY plays an important role in energy balance and responds to changes in energy status. For example, NPY increases during food deprivation and returns to baseline levels following refeeding in the hypothalamic ARC and paraventricular nucleus (PVN) (1, 2, 29).Hypothalamic NPY also responds to changes in energy status signals, as it decreases with elevated leptin or insulin levels and increases with elevated ghrelin, growth hormone, or glucocorticoid levels (69). In addition, rodent models of genetic obesity including the fa/fa Zucker rat as well as db/db and ob/ob mice demonstrate increased hypothalamic...