Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it.

Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations — 7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency. CONCLUSIONS The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, earlyonset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.

/pdf/clinical-and-molecular-genetic-spectrum-of-congenital-5fddyu26w3.pdf

Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.

Considerable attention has focused on deciphering the hypothalamic pathways that mediate the behavioral and metabolic effects of leptin. We and others have identified several single gene defects that disrupt the molecules in the leptin-melanocortin pathway causing severe obesity in humans. In this review, we consider these human monogenic obesity syndromes and discuss how far the characterization of these patients has informed our understanding of the physiological role of leptin and the melanocortins in the regulation of human body weight and neuroendocrine function.

/pdf/genetics-of-obesity-in-humans-79ve9tpn6m.pdf

Genetics of Obesity in Humans

Over the past twenty years a growing number of genes have been described in which loss of function mutations are consistently associated with the development of severe obesity beginning in early childhood. Whilst individually these disorders are rare, cumulatively at least 10% of children with severe obesity have rare chromosomal abnormalities, nonsense mutations, or missense mutations that strongly drive the carrier’s risk of becoming obese. The diagnosis of a genetic obesity syndrome can provide information that has value for the patient and their family and may help them deal with the social stigma that comes with severe obesity in childhood. In some cases, the finding of a genetic cause for a patient’s obesity can lead to specific therapeutic interventions.

The Genetics of Obesity in Humans

During pregnancy, the mother must adapt her body systems to support nutrient and oxygen supply for growth of the baby in utero and during the subsequent lactation. These include changes in the cardiovascular, pulmonary, immune and metabolic systems of the mother. Failure to appropriately adjust maternal physiology to the pregnant state may result in pregnancy complications, including gestational diabetes and abnormal birth weight, which can further lead to a range of medically significant complications for the mother and baby. The placenta, which forms the functional interface separating the maternal and fetal circulations, is important for mediating adaptations in maternal physiology. It secretes a plethora of hormones into the maternal circulation which modulate her physiology and transfers the oxygen and nutrients available to the fetus for growth. Among these placental hormones, the prolactin-growth hormone family, steroids and neuropeptides play critical roles in driving maternal physiological adaptations during pregnancy. This review examines the changes that occur in maternal physiology in response to pregnancy and the significance of placental hormone production in mediating such changes.

/pdf/the-role-of-placental-hormones-in-mediating-maternal-58kkdb3ehs.pdf

The Role of Placental Hormones in Mediating Maternal Adaptations to Support Pregnancy and Lactation

In an effort to understand the genetics of human obesity, we have studied the physiology and molecular genetics of rodent models with monogenetic forms of obesity including the leptin gene-defectiv...

Heterozygosity forLepob orLeprdb affects body composition and leptin homeostasis in adult mice

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Heterozygosity forLepob orLeprdb affects body composition and leptin homeostasis in adult mice