Regulation of Lean Mass, Bone Mass, and Exercise Tolerance by the Central Melanocortin System

Signaling via the type 4-melanocortin receptor (MC4R) is an important determinant of body weight in mice and humans, where loss of function mutations lead to significant obesity. Humans with mutations in the MC4R experience an increase in lean mass. However, the simultaneous accrual of fat mass in such individuals may contribute to this effect via mechanical loading. We therefore examined the relationship of fat mass and lean mass in mice lacking the type-4 melanocortin receptor (MC4RKO). We demonstrate that MC4RKO mice display increased lean body mass. Further, this is not dependent on changes in adipose mass, as MC4RKO mice possess more lean body mass than diet-induced obese (DIO) wild type mice with equivalent fat mass. To examine potential sources of the increased lean mass in MC4RKO mice, bone mass and strength were examined in MC4RKO mice. Both parameters increase with age in MC4RKO mice, which likely contributes to increases in lean body mass. We functionally characterized the increased lean mass in MC4RKO mice by examining their capacity for treadmill running. MC4R deficiency results in a decrease in exercise performance. No changes in the ratio of oxidative to glycolytic fibers were seen, however MC4RKO mice demonstrate a significantly reduced heart rate, which may underlie their impaired exercise performance. The reduced exercise capacity we report in the MC4RKO mouse has potential clinical ramifications, as efforts to control body weight in humans with melanocortin deficiency may be ineffective due to poor tolerance for physical activity

Sexual Abuse in Childhood and Physical and Mental Health in Adulthood: An Australian Population Study

Although childhood sexual abuse (CSA) is associated with a wide range of health problems later in life, there is also evidence of substantial individual differences. This study describes the mental and physical health of a population sample of Australians, randomly selected from the Commonwealth electoral roll, who have reported their CSA histories. Some 58% of those located from the electoral roll agreed to a telephone interview (n = 1,784). Health status was measured using the Short Form 36 questionnaire. Men who had experienced non-penetrative and penetrative sexual abuse in childhood had 2.25 (95% CI = 1.32-3.82) and 5.93 (95% CI = 2.72-12.95) times respectively the rate of impaired mental health, but no higher rates of impaired physical health. Women who had experienced non-penetrative and penetrative sexual abuse in childhood had 1.87 (95% CI = 1.19-2.95) and 3.15 (95% CI = 1.87-5.33) times respectively the rate of impaired mental health and 1.87 (95% CI = 1.19-2.92) and 2.31 (95% CI = 1.34-3.97) times respectively the rate of impaired physical health. However, participants who had experienced CSA were no less likely than those who had not experienced CSA to be in optimum physical and mental health. None of the possible confounding or moderating variables tested appeared to mitigate the impact of CSA on health outcomes. Those with the highest levels of mental and physical health appear to be unaffected by the experience of CSA

Azole-resistant Aspergillus fumigatus is highly prevalent in the environment of Vietnam, with marked variability by land use type

Azole-resistant environmental Aspergillus fumigatus presents a threat to public health but the extent of this threat in Southeast Asia is poorly described. We conducted environmental surveillance in the Mekong Delta region of Vietnam, collecting air and ground samples across key land-use types, and determined antifungal susceptibilities of Aspergillus section Fumigati (ASF) isolates and azole concentrations in soils. Of 119 ASF isolates, 55% were resistant (or non-wild type) to itraconazole, 65% to posaconazole and 50% to voriconazole. Azole resistance was more frequent in A. fumigatus sensu stricto isolates (95%) than other ASF species (32%). Resistant isolates and agricultural azole residues were overrepresented in samples from cultivated land. cyp51A gene sequence analysis showed 38/56 resistant A. fumigatus sensu stricto isolates carried known resistance mutations, with TR34/L98H most frequent (34/38)

MC4RKO Mice Rapidly Accrue Lean Mass Independent from Fat Mass.

<p>(<b>A</b>) Body weights of 7-week-old male MC4RKO mice (n = 20) were compared with age and weight matched WT mice (n = 10). (<b>B</b>) MC4RKO mice have increased fat mass, (<b>C</b>) but normal lean mass. (<b>D</b>) Fat mass as a percentage of body weight (BW) is increased in MC4RKO mice. (<b>E</b>) Lean mass as a percentage of body weight is unaltered in MC4RKO mice. A subset of WT mice (n = 13) were placed on HFD (DIO-WT) for 4 weeks, from 8–12 weeks of age, while the remainder (n = 7) were maintained on a low fat control diet (Chow-WT). MC4RKO mice were maintained on a low fat control diet during this time. (<b>F</b>) MC4RKO mice weighed more at 12 weeks of age than DIO-WT mice. (<b>G)</b> MC4RKO mice have equivalent fat mass at 12 weeks of age compared with DIO-WT mice. (<b>H</b>) MC4RKO mice have increased lean mass relative to DIO-WT mice at 12 weeks of age. (<b>I</b>) Mice fed a HFD for 4 weeks gain an equivalent amount of fat mass as MC4RKO mice. (<b>J</b>) MC4RKO mice gain more lean mass than DIO-WT mice. (<b>K</b>) % body fat, (<b>L</b>) and % lean mass. Data represented as mean ± s.e.m. ** = P<0.01, *** = P<0.001 as calculated by unpaired t-test or one-way ANOVA with a Bonferroni post test.</p

Skeletal Phenotype of WT and MC4RKO Mice at 40 Weeks.

<p>The skeletal phenotype of forty-week-old female WT (n = 11) and MC4RKO mice (n = 12) was examined by DEXA and microtomography. Bone strength was determined by 3 point bending to failure. Vertebral morphometric variables describing bone microstructure were computed using direct 3D methods. Values are represented as mean ± SEM. Statistical significance was assessed by Students t-test, with significant differences assigned a p value<0.05.</p

Trabecular bone microarchitecture of WT and MC4RKO mice at 40 Weeks.

<p>Two-dimensional frontal planar <i>μ</i>CT images of the fifth vertebral body were obtained as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042183#s4" target="_blank">Methods</a> sections.</p

Mice lacking the type 4 melanocortin receptor have a normal muscle fiber type distribution with a decreased resting heart rate.

<p>Skeletal and cardiac muscle was examined in in 11-week old male WT (n = 5) and MC4RKO (n = 6) mice. (<b>A</b>) Resting heart rate was decreased in MC4RKO mice. (<b>B</b>) Cardiac gene expression in male MC4RKO and aged matched control mice at 35 weeks of age (n = 5–6/group). (<b>C–E</b>) No differences were seen in type I fiber number in the soleus, (<b>F–H</b>) type IIa fibers in the soleus or (<b>I–K</b>) type IIa fibers in the gastrocnemius. Scale bar = 100 µm. * = P<0.05, *** = P<0.001 as calculated by unpaired t-test.</p