I S FAROOQI and SO’RAHILLY Human disorders of leptin action 223:1 T63–T70 Thematic Review 20 YEARS OF LEPTIN Human disorders of leptin action I Sadaf Farooqi and Stephen O’Rahilly Correspondence should be addressed to MRC Metabolic Diseases Unit, Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic I S Farooqi Science, NIHR Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, University of Cambridge, Email Cambridge, UK [email protected] Abstract The discovery of leptin has provided a robust framework upon which our current Key Words understanding of the mechanisms involved in energy homeostasis has been built. In this " leptin review, we describe how the identification of humans with mutations in the genes encoding " receptors leptin and the leptin receptor and the characterisation of the associated clinical phenotypes " obesity have provided insights into the role of leptin-responsive pathways in the regulation of " signal transduction eating behaviour, intermediary metabolism and the onset of puberty. Importantly, administration of recombinant human leptin in leptin deficiency represents the first mechanistically based targeted therapy for obesity and has provided immense clinical benefits for the patients concerned. In subsequent years, we and others have shown that human obesity can result from a multiplicity of defects in the pathways downstream of leptin signalling within the brain. Journal of Endocrinology (2014) 223, T63–T70 Journal of Endocrinology Discovery of mutations in leptin and (Strobel et al. 1998) and since that time, several other the leptin receptor in humans affected individuals from consanguineous families (Farooqi et al. 2002, Mazen et al. 2009, Frank et al. 2011, Early studies carried out in obese humans showed that Saeed et al. 2012; and I S Farooqi, unpublished obser- leptin mRNA concentrations in adipose tissue and serum vations) have been studied. Clement et al. (1998) identified leptin concentrations correlated positively and very the first patients with homozygous mutations in the gene closely with the amount of fat mass (Maffei et al. 1995, LEPR Considine et al. 1996). In 1997, we studied two severely encoding the leptin receptor ( ) in 1998. Additional obese cousins from a highly consanguineous UK family homozygous frameshift, nonsense and missense LEPR w of Pakistani origin, in whom the known central mutations have been identified in 2–3% of severely and endocrine causes of obesity had been excluded obese patients from consanguineous families (Farooqi et al. (Montague et al. 1997). Being aware of Friedman’s work 2007a, Mazen et al. 2011). LEPR mutations have been (Zhang et al. 1994), we measured the serum leptin found in some non-consanguineous families, where both concentration in these children and found that they had parents were unrelated but carried rare heterozygous alleles undetectable leptin concentrations despite their severe that result in a loss of function (Farooqi et al. 2007a). obesity and were homozygous for a frameshift mutation in Analysis of serum leptin levels is a useful test in the LEP gene, which resulted in a truncated protein that patients with severe early-onset obesity because an was not secreted (Montague et al. 1997). In 1998, three undetectable serum leptin level is highly suggestive of a adults carrying a homozygous missense mutation in the diagnosis of congenital leptin deficiency. It is plausible, LEP gene were reported in a family of Turkish origin that mutations in the LEP gene could result in a http://joe.endocrinology-journals.org Ñ 2014 Society for Endocrinology This paper is part of a thematic review section on 20 Years of Leptin. The Guest Editor DOI: 10.1530/JOE-14-0480 Printed in Great Britain for this section was Sir Stephen O’Rahilly, University of Cambridge, Cambridge, UK. He Published by Bioscientifica Ltd. was not involved in the handling ofDownloaded this paper, from on which Bioscientifica.com he is listed as at an 09/24/2021 author 12:08:24PM via free access Thematic Review I S FAROOQI and SO’RAHILLY Human disorders of leptin action 223:1 T64 bio-inactive form of the hormone in the presence of of obesity. Some adults have developed type 2 diabetes in apparently appropriate leptin levels; however, no such the third to fourth decade (Strobel et al, 1998). cases have been reported to date and, based on comparable Leptin and LEPR deficiency are associated with hormone deficiency syndromes, if they do exist, such hypothalamic hypothyroidism characterised by a low patients are likely to be very rare. free thyroxine (T4) and a high serum thyroid-stimulating Serum leptin concentrations are appropriate for the hormone (TSH) levels which are bio-inactive (Farooqi degree of obesity in LEPR-deficient patients and as such et al. 2002). The pulsatility of TSH secretion, studied in an elevated serum leptin concentration is not necessarily a single adult with congenital leptin deficiency, was a predictor of LEPR deficiency (Farooqi et al. 2007a). characterised by a markedly disorganised secretory However, in some patients, particularly LEPR mutations pattern (Mantzoros et al. 2001). Generally, normal that result in abnormal cleavage of the extracellular pubertal development does not occur in adults with domain of LEPR (which then can act as a leptin-binding leptin or LEPR deficiency (Strobel et al. 1998), with protein) are associated with markedly elevated leptin biochemical evidence of hypogonadotropic hypogonad- levels (Clement et al. 1998, Lahlou et al. 2000). ism (von Schnurbein et al. 2012). However, there is some evidence for the delayed but spontaneous onset of Characteristic clinical features seen in leptin menses in a small number of leptin and LEPR-deficient and LEPR deficiency adults (Farooqi et al. 2007a); the mechanisms underlying this are unclear. Linear growth is appropriate in child- The clinical phenotypes associated with leptin and LEPR hood; however, due to the absence of a pubertal growth deficiencies are broadly similar (Montague et al. 1997, spurt, final height is reduced. Ozata et al. 1999, Farooqi et al. 2007a). Patients are born of normal birth weight but exhibit rapid weight gain in the first few months of life, resulting in severe obesity (mean BMI SDS: 5.8–7.8). The patients often have a distinctive Response to leptin administration in leptin clinical appearance with excessive amounts of subcu- deficiency taneous fat over the trunk and limbs. Body composition Although leptin deficiency is rare, it is entirely treatable measurements have shown that these disorders are with daily s.c. injections of recombinant human leptin characterised by the preferential deposition of fat mass; Journal of Endocrinology (Farooqi et al. 1999, Licinio et al. 2004). Such treatment is indeed the mean percentage body fat among homozygous currently available to patients on a named-patient basis. carriers of LEP mutations is very high at 58% (compared In 1997, we started the first clinical trial administering with 45% for equally obese children of the same age daily injections of recombinant human leptin to leptin- (Farooqi et al. 2007a)). deficient patients, (Farooqi et al. 1999) with the support of In the clinical history, early development is usually Amgen, Inc. (Thousand Oaks, CA, USA) and subsequently normal. The most notable feature is intense hyperphagia Amylin Pharmaceuticals, Inc. (San Diego, CA, USA) and with food-seeking behaviour and aggressive behaviour Bristol Myers Squibb/AstraZeneca. Recombinant leptin when food is denied. In the research setting, measure- ments of energy intake at ad libitum test meals reveal the therapy led to remarkable beneficial effects for the extent of hyperphagia with food intake three to five times leptin-deficient patients (Fig. 1) and provided proof of that of children of the same age with both an increase principle for the pivotal role of leptin action in humans in hunger and impaired satiety seen after meals of fixed (Farooqi et al. 1999, 2002). Studies carried out in patients quantity and composition (Farooqi et al. 2002). Increased with congenital leptin deficiency before and after treat- food-seeking behaviour continues into later life in the ment with leptin paved the way for understanding the adult subjects who have been reported (Ozata et al. 1999). major actions of leptin in humans, which have been Children with leptin deficiency have marked abnormal- supported and extended by elegant studies carried out by ities of T cell number and function (Farooqi et al. 2002), many investigators in normal weight and obese volunteers consistent with high rates of childhood infection and a in the context of fasting or a weight-reduced state high reported rate of childhood mortality from infection (Rosenbaum et al. 2002, 2005) and in patients with (Ozata et al. 1999). In those who survive, obesity continues lipodystrophic syndromes characterised by partial in adult life, with hepatic steatosis (von Schnurbein et al. leptin deficiency due to a loss of adipose tissue mass 2013) and hyperinsulinaemia consistent with the severity (Oral et al. 2002). http://joe.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd DOI: 10.1530/JOE-14-0480 Printed in Great Britain Downloaded from Bioscientifica.com at 09/24/2021 12:08:24PM via free access Thematic Review I S FAROOQI and SO’RAHILLY Human disorders of leptin action 223:1 T65 for food images; to examine the interaction with eating, we studied two subjects in the fasted state and after eating (Farooqi et al. 2007b). In the leptin-deficient state, images of food (compared with non-food items) were associated with a marked increase in neuronal activation in the anteromedial ventral striatum (nucleus accumbens and caudate nucleus) and the posterolateral ventral striatum (putamen and globus pallidus), which are areas associated with pleasure and reward. This response was normalised by 7 days of leptin treatment, before weight loss occurred. When asked to rate how much they liked each of the food images, leptin-deficient subjects gave high ratings to all food images in both the fasted and fed states (Farooqi et al.