The central melanocortin system directly controls peripheral lipid metabolism

Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role of the central nervous melanocortin system (CNS-Mcr) in the control of adiposity through effects on nutrient partitioning and cellular lipid metabolism independent of nutrient intake. We report that pharmacological inhibition of melanocortin receptors (Mcr) in rats and genetic disruption of Mc4r in mice directly and potently promoted lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue (WAT), while increased CNS-Mcr signaling triggered lipid mobilization. These effects were independent of food intake and preceded changes in adiposity. In addition, decreased CNS-Mcr signaling promoted increased insulin sensitivity and glucose uptake in WAT while decreasing glucose utilization in muscle and brown adipose tissue. Such CNS control of peripheral nutrient partitioning depended on sympathetic nervous system function and was enhanced by synergistic effects on liver triglyceride synthesis. Our findings offer an explanation for enhanced adiposity resulting from decreased melanocortin signaling, even in the absence of hyperphagia, and are consistent with feeding-independent changes in substrate utilization as reflected by respiratory quotient, which is increased with chronic Mcr blockade in rodents and in humans with loss-of-function mutations in MC4R. We also reveal molecular underpinnings for direct control of the CNS-Mcr over lipid metabolism. These results suggest ways to design more efficient pharmacological methods for controlling adiposity.     

Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis

Selenium is a trace element that is essential for human health and is incorporated into more than 25 human selenocysteine-containing (Sec-containing) proteins via unique Sec-insertion machinery that includes a specific, nuclear genome–encoded, transfer RNA (tRNA^[Ser]Sec). Here, we have identified a human tRNA^[Ser]Sec mutation in a proband who presented with a variety of symptoms, including abdominal pain, fatigue, muscle weakness, and low plasma levels of selenium. This mutation resulted in a marked reduction in expression of stress-related, but not housekeeping, selenoproteins. Evaluation of primary cells from the homozygous proband and a heterozygous parent indicated that the observed deficit in stress-related selenoprotein production is likely mediated by reduced expression and diminished 2′-O-methylribosylation at uridine 34 in mutant tRNA^[Ser]Sec. Moreover, this methylribosylation defect was restored by cellular complementation with normal tRNA^[Ser]Sec. This study identifies a tRNA mutation that selectively impairs synthesis of stress-related selenoproteins and demonstrates the importance of tRNA modification for normal selenoprotein synthesis.     

Prevalence, risk factors and virological profile of chronic hepatitis B virus infection in pregnant women in India

A large program was conducted by the Government of India to study the prevalence and profile of chronic hepatitis B virus (HBV) infection and its risk factors in pregnant women attending a tertiary care hospital in India. From September 2004 to December 2008 consecutive pregnant women attending the antenatal clinic were screened and those found positive for HBsAg were enrolled. Healthy non‐pregnant women of child‐bearing age, who presented for blood donation during the same period, served as controls. Women with symptoms of liver disease or those aware of their HBsAg status were excluded. Of the 20,104 pregnant women screened, 224 (1.1%) and of the 658 controls, 8 (1.2%) were HBsAg positive (P = ns). Previous blood transfusions and surgery were significant risk factors for infection with HBV. Of the women who were HBsAg positive, the ALT levels were normal in 54% of the women and HBV DNA levels were above 2,000 IU/ml in 71% of women. The median HBV DNA levels were higher in women who were HBeAg positive compared to the HBeAg negative group. The most common HBV genotype was D (84%) followed by A + D and A (8% each). In conclusion, the prevalence of HBsAg positivity among asymptomatic pregnant women in North India is 1.1% with 71% having high HBV DNA levels. These women may have a high risk of transmitting infection to their newborns. J. Med. Virol. 83:962–967, 2011. © 2011 Wiley‐Liss, Inc.     

Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees

OBJECTIVE— Melanocortin-4 receptor (MC4R) deficiency is the most frequent genetic cause of obesity. However, there is uncertainty regarding the degree of penetrance of this condition, and the putative impact of the environment on the development of obesity in MC4R mutation carriers is unknown.RESEARCH DESIGN AND METHODS— We determined the MC4R sequence in 2,257 obese individuals and 2,677 nonobese control subjects of European origin and established the likely functional impact of all variants detected. We then included relatives of probands carriers and studied 25 pedigrees, including 97 carriers and 94 noncarriers from three generations.RESULTS— Of the MC4R nonsynonymous mutations found in obese subjects, 68% resulted in a loss of function in vitro. They were found in 1.72% of obese versus 0.15% of nonobesed subjects (P = 6.9 × 10⁻¹⁰). Among the families, abnormal eating behavior was more frequent in both MC4R-deficient children and adults than in noncarriers. Although BMI was inversely associated with educational status in noncarrier adults, no such relationship was seen in MC4R mutation carriers. We observed a generational effect, with a penetrance of 40% in MC4R-deficient adults aged >52 years, 60% in 18- to 52-year-old adults, and 79% in children. The longitudinal study of adult carriers showed an increasing age-dependent penetrance (37% at 20 years versus 60% at >40 years).CONCLUSIONS— We have established a robust estimate of age-related penetrance for MC4R deficiency and demonstrated a generational effect on penetrance, which may relate to the development of an “obesogenic” environment. It remains to be seen whether appropriate manipulation of environmental factors may contribute to preventing the development of obesity even in those strongly genetically predisposed to it.The leptin-melanocortin axis controls human energy homeostasis, and the melanocortin-4 receptor (MC4R) is a key player in its central regulation (1). Loss-of-function mutations in MC4R cause severe familial forms of obesity (2,3), and infrequent gain-of-function polymorphisms have been associated with protection against obesity (4,5). At least 72 nonsynonymous mutations have been discovered so far, but some have no obvious functional consequences (6,7), highlighting the importance of functional characterization of MC4R mutations in the determination of potential pathogenicity. MC4R is a membrane-bound G-protein–coupled receptor that activates adenylate cyclase. Loss-of-function mutations result in a partial or complete loss of function as measured by cAMP production. The majority of missense mutations in MC4R result in intracellular retention of the mutated protein, whereas some primarily affect ligand binding or ligand/receptor activation (8,9). In some cases, the alteration of the basal activity of the receptor (8,10) has been reported.The prevalence of loss-of-function MC4R mutations ranges from 0.5 to 5.8% in childhood-onset obesity (11–14). The contribution of MC4R mutations to late-onset obesity is still debated (13,15–18). Obesity due to MC4R mutations has been extensively studied, and although heterozygous loss-of-function mutations can clearly cause familial obesity, they can be found in individuals who are not obese (19). There is a need for reliable estimates of penetrance. Furthermore, no study has thoroughly assessed the effect of loss-of-function MC4R mutations in elderly subjects. Previous studies using part of our French cohort evidenced the first mutation in MC4R and demonstrated that most of them lead to an intracellular retention of the receptor (2,13,18).Although hyperphagia is a key feature of MC4R deficiency, with increased food intake at an ad libitum test meal reported in severely obese MC4R-deficient children (10), an apparent amelioration of obesity and food intake disturbances has been suggested in adulthood in some studies (6,11). Obesity is a complex trait, and MC4R mutations offer a unique opportunity to analyze the effects of both aging and shared environment on the evolution of body mass in this paradigm. In this extensive study of 2,257 unrelated obese subjects, 2,677 control subjects of European descent, and 25 multigenerational pedigrees with several MC4R mutations carriers, we provide a comprehensive picture of the prevalence of this condition and of factors that determine the expression of the obesity phenotype and support previous observations reported in a German familial study (20).     

Melanocortin receptors as targets in the treatment of obesity

The central melanocortin system plays a critical role in energy homeostasis. It is well established that melanocortin-containing neurons are nutritionally regulated and that genetic alterations in the melanocortin system produce profound effects on food intake, energy expenditure, and body weight. Within the brain, melanocortin-producing neurons originate in the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the solitary tract (NTS) in the brainstem and project to various nuclei modulating energy balance. A large body of pharmacological and genetic evidence implicates the central melanocortin 4 receptors (MC4Rs) in the effects of melanocortin peptides on ingestive behaviour, energy expenditure, and body weight. Preclinical studies with endogenous and synthetic melanocortin ligands demonstrate that they produce potent effects on food intake and energy expenditure. Clinical studies thus far have been somewhat less successful and have been hampered by the induction of side effects, which present obstacles to the development of successful therapeutic agents. However, various promising strategies are being pursued to overcome these limitations, including the synthesis of more selective and potent melanocortin analogs.     

Investigation of white blood cell characteristics in cerebrospinal fluid samples at pediatric brain tumor diagnosis

Journal of Neuro-Oncology - The role of white blood cells (WBC) in the pediatric central nervous system (CNS) tumor microenvironment is incompletely defined. We hypothesized that the WBC profile in...     

Community Attachments are Associated with COVID-19 Public Health Behaviors Among Adolescents in Pakistan

Child & Youth Care Forum - Community attachments are thought to promote adolescents’ engagement in public health behaviors. To date, past research has exclusively examined the social...