weight. the reason for this may be high levels of triglycerides affecting the transport of leptin across the bbb or due to the leptin transporter becoming saturated. although deficits in the transfer of leptin from the plasma to the csf is seen in obese people, they are still found to have 30% more leptin in their csf than lean individuals. these higher csf levels fail to prevent their obesity. since the amount and quality of leptin receptors in the hypothalamus appears to be normal in the majority of obese humans (as judged from leptin-mrna studies), it is likely that the leptin resistance in these individuals is due to a post leptin-receptor deficit, similar to the post-insulin receptor defect seen in type 2 diabetes. when leptin binds with the leptin receptor, it activates a number of pathways. leptin resistance may be caused by defects in one or more parts of this process, particularly the jak/stat pathway. mice with a mutation in the leptin receptor gene that prevents the activation of stat3 are obese and exhibit hyperphagia. the pi3k pathway may also be involved in leptin resistance, as has been demonstrated in mice by artificial blocking of pi3k signalling. the pi3k pathway also is activated by the insulin receptor and is therefore an important area where leptin and insulin act together as part of energy homeostasis. the insulin-pi3k pathway can cause pomc neurons to become insensitive to leptin through hyperpolarization. leptin is known to interact with amylin, a hormone involved in gastric emptying and creating a feeling of fullness. when both leptin and amylin were given to obese, leptin-resistant rats, sustained weight loss was seen. due to its apparent ability to reverse leptin resistance, amylin has been suggested as possible therapy for obesity. it has been suggested that the main role of leptin is to act as a starvation signal when levels are low, to help maintain fat stores for survival during times of starvation, rather than a satiety signal to prevent overeating. leptin levels signal when an animal has enough stored energy to spend it in pursuits besides acquiring food. this would mean that leptin resistance in obese people is a normal part of mammalian physiology and possibly, could confer a survival advantage. leptin resistance (in combination with insulin resistance and weight gain) is seen in rats after they are given unlimited access to palatable, energy-dense foods. this effect is reversed when the animals are put back on a low-energy diet. this also may have an evolutionary advantage: allowing energy to be stored efficiently when food is plentiful would be advantageous in populations where food frequently may be scarce. a fad diet, the rosedale diet is based on ideas about how leptin might affect weight. it is based on unsound science and marketed with unevidenced claims of health benefits. obesity and osteoarthritis osteoarthritis and obesity are closely linked. obesity is one of the most important preventable factors for the development of osteoarthritis. originally, the relationship between osteoarthritis and obesity was considered to be exclusively biomechanically based, according to which the excess weight caused the joint to become worn down more quickly. however, today we recognise that there is also a metabolic component which explains why obesity is a risk factor for osteoarthritis, not only for weight-bearing joints (for example, the knees), but also for joints that do not bear weight (for example, the hands). consequently, it has been shown that decreasing body fat lessens osteoarthritis to a greater extent than weight loss per se. this metabolic component related with the release of systemic factors, of a pro-inflammatory nature, by the adipose tissues, which frequently are critically associated with the development of osteoarthritis. thus, the deregulated production of adipokines and inflammatory mediators, hyperlipidaemia, and the increase of systemic oxidative stress are conditions frequently associated with obesity which can favour joint degeneration. furthermore, many regulation factors have been implicated in the development, maintenance and function, both of adipose tissues, as well as of the cartilage and other joint tissues. alterations in these factors can be the additional link between obesity and osteoarthritis. leptin and osteoarthritis adipocytes interact with other cells through producing and secreting a variety of signalling molecules, including the cell signalling proteins known as adipokines. certain adipokines can be considered as hormones, as they regulate the functions of organs at a distance, and several of them have been specifically involved in the physiopathology of joint diseases. in particular, there is one, leptin, which has been the focus of attention for research in recent years. the circulating leptin levels are positively correlated with the body mass index (bmi), more specifically with fatty mass, and obese individuals have higher leptin levels in their blood circulation, compared with non-obese individuals. in obese individuals, the increased circulating leptin levels induce unwanted responses, that is, reduced food intake or losing body weight does not occur as there is a resistance to leptin (ref 9). in addition to the function of regulating energy homeostasis, leptin carries out a role in other physiological functions such as neuroendocrine communication, reproduction, angiogenesis and bone formation. more recently, leptin has been recognised as a cytokine factor as well as with pleiotropic actions also in the immune response and inflammation. for example, leptin can be found in the synovial fluid in correlation with the body mass index, and the leptin receptors are expressed in the cartilage, where leptin mediates and modulates many inflammatory responses that can damage cartilage and other joint tissues. leptin has thus emerged as a candidate to link obesity and osteoarthritis and serves as an apparent objective as a nutritional treatment for osteoarthritis. as in the plasma, the leptin levels in the synovial fluid are positively correlated with bmi. the leptin of the synovial fluid is synthesised at least partially in the joint and may originate in part in the circulation. leptin has been shown to be produced by chondrocytes, as well as by other tissues in the joints, including the synovial tissue, osteophytes, the meniscus and bone. an infrapatellar fat pad located extrasynovially within the knee joint is also adjacent to the synovial membrane and cartilage, and has recently been highly appreciated as an important source of leptin, as well as other adipokines and mediators which contribute to the pathogenesis of osteoarthritis the risk of suffering osteoarthritis can be decreased with weight loss. this reduction of risk is related in part with the decrease of the load on the joint, but also in the decrease of fatty mass, the central adipose tissue and the low-level inflammation associated with obesity and systemic factors. this growing evidence points to leptin as a cartilage degradation factor in the pathogenesis of osteoarthritis, and as a potential biomarker in the progression of the disease, which suggests that leptin, as well as regulation and signalling mechanisms, can be a new and promising target in the treatment of osteoarthritis, especially in obese patients. obese individuals are predisposed to developing osteoarthritis, not only due to the excess mechanical load, but also due to the excess expression of soluble factors, that is, leptin and pro-inflammatory cytokines, which contribute to joint inflammation and cartilage destruction. as such, obese individuals are in an altered state, due to a metabolic insufficiency, which requires specific nutritional treatment capable of normalising the leptin production and reducing the systematic low-level inflammation, in order to reduce the harmful impact of these systematic mediators on the joint health. there are nutritional supplements and pharmacological agents capable of directing these factors and improving both conditions. therapeutic use leptin leptin was approved in the united states in 2014 for use in congenital leptin deficiency and generalized lipodystrophy. analog metreleptin main article: metreleptin an analog of human leptin metreleptin (trade names myalept, myalepta) was first approved in japan in 2013, and in the united states in february 2014 and in europe in 2018. in the us it is indicated as a treatment for complications of leptin deficiency, and for the diabetes and hypertriglyceridemia associated with congenital or acquired generalized lipodystrophy. in europe based on ema, metreleptin should be used in addition to diet to treat lipodystrophy, where patients have loss of fatty tissue under the skin and build-up of fat elsewhere in the body such as in the liver and muscles. the medicine is used in adults and children above the age of 2 years with generalised lipodystrophy (berardinelli-seip syndrome and lawrence syndrome); and in adults and children above the age of 12 years with partial lipodystrophy (including barraquer-simons syndrome), when standard treatments have failed. the national health service in england will commission metreleptin treatment for all with congenital leptin deficiency regardless of age beginning on april 1, 2019. research leptin is currently being evaluated as a potential target for the treatment of anorexia nervosa. it is hypothesized that the gradual loss of body fat mass, and more specifically the ensuing low leptin levels, escalate the preexisting drive for thinness into an obsessive-compulsive-like and addictive-like state. it was shown that short-term metreleptin treatment of patients with anorexia nervosa had rapid on-set of beneficial cognitive, emotional, and behavioral effects. among other things, depression, drive for activity, repetitive thoughts of food, inner restlessness, and weight phobia decreased rapidly. whether metreleptin (or another leptin analogue) is a suitable treatment for anorexia nervosa is currently unknown. potential side effects are weight loss and the development of anti-metreleptin antibodies. history the leptine was discovered by jeffrey friedman in 1994 after several decades of research conducted by others institutions since 1950 on obese mouse models identification of the encoding gene in 1949, a non-obese mouse colony being studied at the jackson laboratory produced a strain of obese offspring, suggesting that a mutation had occurred in a hormone regulating hunger and energy expenditure. mice homozygous for the so-called ob mutation (ob/ob) ate voraciously and were massively obese. in the 1960s, a second mutation causing obesity and a similar phenotype was identified by douglas coleman, also at the jackson laboratory, and was named diabetes (db), as both ob/ob and db/db were obese. in 1990 rudolph leibel and jeffrey m. friedman reported mapping of the db gene. consistent with coleman's and leibel's hypothesis, several subsequent studies from leibel's and friedman's labs and other groups confirmed that the ob gene encoded a novel hormone that circulated in blood and that could suppress food intake and body weight in ob and wild type mice, but not in db mice. in 1994, friedman's laboratory reported the identification of the gene. in 1995, jose f. caro's laboratory provided evidence that the mutations in the mouse ob gene did not occur in humans. furthermore, since ob gene expression was increased, not decreased, in human obesity, it suggested resistance to leptin to be a possibility. at the suggestion of roger guillemin, friedman named this new hormone "leptin" from the greek lepto meaning thin. leptin was the first fat cell-derived hormone (adipokine) to be discovered. subsequent studies in 1995 confirmed that the db gene encodes the leptin receptor, and that it is expressed in the hypothalamus, a region of the brain known to regulate the sensation of hunger and body weight. recognition of scientific advances coleman and friedman have been awarded numerous prizes acknowledging their roles in discovery of leptin, including the gairdner foundation international award (2005), the shaw prize (2009), the lasker award, the bbva foundation frontiers of knowledge award and the king faisal international prize, leibel has not received the same level of recognition from the discovery because he was omitted as a co-author of a scientific paper published by friedman that reported the discovery of the gene. the various theories surrounding friedman's omission of leibel and others as co-authors of this paper have been presented in a number of publications, including ellen ruppel shell’s 2002 book the hungry gene. the discovery of leptin also is documented in a series of books including fat: fighting the obesity epidemic by robert pool, the hungry gene by ellen ruppel shell, and rethinking thin: the new science of weight loss and the myths and realities of dieting by gina kolata. fat: fighting the obesity epidemic and rethinking thin: the new science of weight loss and the myths and realities of dieting review the work in the friedman laboratory that led to the cloning of the ob gene, while the hungry gene draws attention