Leptin, discovered through positional cloning 15 years ago, is an adipocyte-secreted hormone with pleiotropic effects in the physiology and pathophysiology of energy homeostasis, endocrinology, and metabolism. Studies in vitro and in animal models highlight the potential for leptin to regulate a number of physiological functions. Available evidence from human studies indicates that leptin has a mainly permissive role, with leptin administration being effective in states of leptin deficiency, less effective in states of leptin adequacy, and largely ineffective in states of leptin excess. Results from interventional studies in humans demonstrate that leptin administration in subjects with congenital complete leptin deficiency or subjects with partial leptin deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions. More specifically, in women with hypothalamic amenorrhea, leptin helps restore abnormalities in hypothalamic-pituitary-peripheral axes including the gonadal, thyroid, growth hormone, and to a lesser extent adrenal axes. Furthermore, leptin results in resumption of menses in the majority of these subjects and, in the long term, may increase bone mineral content and density, especially at the lumbar spine. In patients with congenital or HIVrelated lipoatrophy, leptin treatment is also associated with improvements in insulin sensitivity and lipid profile, concomitant with reduced visceral and ectopic fat deposition. In contrast, leptin's effects are largely absent in the obese hyperleptinemic state, probably due to leptin resistance or tolerance. Hence, another emerging area of research pertains to the discovery and/or usefulness of leptin sensitizers. Results from ongoing studies are expected to further increase our understanding of the role of leptin and the potential clinical applications of leptin or its analogs in human therapeutics. adipokines; adipose tissue; leptin resistance; leptin deficiency; hypoleptinemia STUDIES OF GENETICALLY OBESE MICE serendipitously found in the Jackson Laboratories revealed that their phenotypes derive from homozygous mutations of either the obese (ob) or diabetic (db) genes that result in obesity and insulin resistance or diabetes as well as endocrine and immune dysfunction (53, 54,115,117,183,261). The gene mutation in the ob/ob mouse results in a complete deficiency of or a truncated and biologically inactive ob gene product (287); the latter subsequently was given the name leptin (95), from the Greek word "leptos" (meaning "thin"), because when this protein was given to the obese ob/ob mice they lost significant amounts of body weight. It was then recognized that the db gene codes for the leptin receptor (140). Consequently, exogenously administered leptin reduces body weight and resolves the metabolic, endocrine, and immune disturbances in ob/ob mice but has no effects in db/db mice (100, 111, 28...

Leptin regulates energy homeostasis and reproductive, neuroendocrine, immune, and metabolic functions. In this review, we describe the role of leptin in human physiology and review evidence from recent “proof of concept” clinical trials using recombinant human leptin in subjects with congenital leptin deficiency, hypoleptinemia associated with energy-deficient states, and hyperleptinemia associated with garden-variety obesity. Since most obese individuals are largely leptin-tolerant or -resistant, therapeutic uses of leptin are currently limited to patients with complete or partial leptin deficiency, including hypothalamic amenorrhea and lipoatrophy. Leptin administration in these energy-deficient states may help restore associated neuroendocrine, metabolic, and immune function and bone metabolism. Leptin treatment is currently available for individuals with congenital leptin deficiency and congenital lipoatrophy. The long-term efficacy and safety of leptin treatment in hypothalamic amenorrhea and acquired lipoatrophy are currently under investigation. Whether combination therapy with leptin and potential leptin sensitizers will prove effective in the treatment of garden-variety obesity and whether leptin may have a role in weight loss maintenance is being greatly anticipated.

Reductions in natural frequency are often used as a damage indicator for structural health monitoring (SHM) purposes. However, fluctuations in operational and environmental conditions, changes in boundary conditions, and slight differences among nominally-identical structures can also affect stiffness, producing frequency changes that mimic or mask damage. This variability has limited the practical implementation and generalisation of SHM technologies. The aim of this work is to investigate the effects of normal variation, and to identify methods that account for the resulting uncertainty. This work considers vibration data collected from a set of four healthy full-scale composite helicopter blades. The blades were nominally-identical but distinct, and slight differences in material properties and geometry among the blades caused significant variability in the frequency response functions, which presented as four separate trajectories across the input space. In this paper, an overlapping mixture of Gaussian processes (OMGP), was used to generate labels and quantify the uncertainty of normal-condition frequency response data from the helicopter blades. Using a population-based approach, the OMGP model provided a generic representation, called a form, to characterise the normal condition of the blades. Additional simulated data were then compared against the form and evaluated for damage using a marginal-likelihood novelty index.