20 YEARS OF LEPTIN: Human disorders of leptin action

Farooqi, I. Sadaf; O’Rahilly, Stephen

doi:10.1530/joe-14-0480

Cited by 240 publications

(177 citation statements)

References 55 publications

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“…Unlike most other rodent obesity models used in diabetes research (e.g., ob/ob and db/db mice and certain fa/fa rats) (55-57), our model does not have a mutation in the genes for leptin or its receptor, but leptin signaling is affected, nevertheless. Only a handful of mutations have been identified in human genes encoding leptin or the leptin receptor in patients with obesity and insulin resistance; however, the majority of patients lack such mutations but still demonstrate defects in leptin signaling (58). The severe diabese phenotype found in WeD-fed SNAP-25b-deficient mice suggests that any polymorphism in genes directly or indirectly regulating Ca 2+ -dependent membrane fusion potentially could be associated with an increased risk of developing metabolic disease, especially in combination with increased calorie intake and insufficient physical activity.…”

Section: (E and F) Hypothalamic Pstat3 Is Decreased In All Experimentmentioning

confidence: 99%

Replacing SNAP-25b with SNAP-25a expression results in metabolic disease

Valladolid‐Acebes

Daraio

Brismar

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Synaptosomal-associated protein of 25 kDa (SNAP-25) is a key molecule in the soluble N-ethylmaleimide-sensitive factor attachment protein (SNARE) complex mediating fast Ca 2+ -triggered release of hormones and neurotransmitters, and both splice variants, SNAP-25a and SNAP-25b, can participate in this process. Here we explore the hypothesis that minor alterations in the machinery mediating regulated membrane fusion can increase the susceptibility for metabolic disease and precede obesity and type 2 diabetes. Thus, we used a mouse mutant engineered to express normal levels of SNAP-25 but only SNAP-25a. These SNAP-25b-deficient mice were exposed to either a control or a high-fat/high-sucrose diet. Monitoring of food intake, body weight, hypothalamic function, and lipid and glucose homeostases showed that SNAP-25b-deficient mice fed with control diet developed hyperglycemia, liver steatosis, and adipocyte hypertrophy, conditions dramatically exacerbated when combined with the high-fat/high-sucrose diet. Thus, modified SNARE function regulating stimulus-dependent exocytosis can increase the vulnerability to and even provoke metabolic disease. When combined with a high-fat/high-sucrose diet, this vulnerability resulted in diabesity. Our SNAP-25b-deficient mouse may represent a diabesity model.O n-going lifestyle changes, including oversized meals with excessive amounts of sugar and fat, have led to a worldwide pandemic of obesity and type 2 diabetes (T2D) (1). These diseases and their comorbidities cause individual suffering and represent a heavy financial burden on society (2, 3). The term "diabesity" is used to define the coincidence of obesity with T2D under conditions of exaggerated intake of energy-dense diets (4-6). Moreover, genomewide association studies (GWAS) have identified polymorphisms associated with obesity and T2D, indicating that genetic factors predispose certain individuals to diabesity (7-11).Signs of metabolic diseases include impaired regulated release of hormones, particularly insulin as in T2D (4, 12). Likewise, the secretion of inflammatory markers and other peripheral bioactive peptides is either increased (e.g., leptin, resistin, and adipsin) or decreased (e.g., ghrelin and adiponectin) (13-16). Synaptic and nonsynaptic transmission involving the release of neuropeptides and neurotransmitters, especially in hypothalamic areas controlling eating behavior and energy balance, are involved too (17)(18)(19).In excitable cells, the release of messenger molecules is a consequence of regulated membrane fusion and involves soluble N-ethylmaleimide-sensitive factor attachment proteins (SNAREs) (20, 21), including synaptosomal-associated protein of 25 kDa (SNAP-25). SNAP-25 is expressed as two developmentally regulated and alternatively spliced isoforms, SNAP-25a and SNAP-25b, which differ in only 9 of 206 amino acids (22, 23). In the mouse brain, SNAP-25a precedes SNAP-25b expression during development, but by the second postnatal week SNAP-25b becomes the major splice variant, concomitantly with a dr...

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Section: (E and F) Hypothalamic Pstat3 Is Decreased In All Experimentmentioning

confidence: 99%

Replacing SNAP-25b with SNAP-25a expression results in metabolic disease

Valladolid‐Acebes

Daraio

Brismar

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The characterisation of the CNS effects of leptin, an adipokine that conveys information about the body's fat stores, circulating levels of which drop with fasting to trigger a concerted CNS response in order to conserve body weight, has revolutionised our understanding of energy homoeostasis (5). Gut hormones such as peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), which are postprandial signals of satiety, cholecystokinin (CCK), which is capable of modulating vagal afferent activity, and ghrelin which is released from the stomach when fasted to act as a powerful meal-inducer, have also been subject to intense research (3).…”

Section: Hormones and Appetitive Behaviourmentioning

confidence: 99%

IMAGING IN ENDOCRINOLOGY: The use of functional MRI to study the endocrinology of appetite

Salem¹,

Dhillo²

2015

European Journal of Endocrinology

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In the present review article, we summarise current thinking about the neuroendocrinology of appetite and feeding behaviour. We discuss how the homeostatic control of energy balance, wherein the hypothalamus orchestrates food intake and energy expenditure in response to peripheral signals about nutritional status, can be easily overridden by the powerful reward value of food. We focus on how functional magnetic resonance imaging has shed light on our understanding of the way hormones can interact with the brain to modulate appetite.

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“…For example, the pups of mice exposed to a high-fat maternal diet during the perinatal period fail to establish neuronal connectivity between the ARH and PVN, resulting in altered body composition and a predisposition to metabolic disease as adults (Vogt et al, 2014). Leptin-deficient (ob/ob) mice and people with mutations in components of the central melanocortin pathway are hyperphagic and obesemaintaining a higher body weight set point owing to leptin deficiency or resistance (reviewed by Farooqi and O'Rahilly, 2014).…”

Section: Energy Homeostasis and Resource Allocation During Pregnancymentioning

confidence: 99%

Genomic imprinting, growth and maternal–fetal interactions

Cassidy

Charalambous

2018

Journal of Experimental Biology

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In the 1980s, mouse nuclear transplantation experiments revealed that both male and female parental genomes are required for successful development to term (McGrath and Solter, 1983; Surani and Barton, 1983). This non-equivalence of parental genomes is because imprinted genes are predominantly expressed from only one parental chromosome. Uniparental inheritance of these genomic regions causes paediatric growth disorders such as Beckwith–Wiedemann and Silver–Russell syndromes (reviewed in Peters, 2014). More than 100 imprinted genes have now been discovered and the functions of many of these genes have been assessed in murine models. The first such genes described were the fetal growth factor insulin-like growth factor 2 (Igf2) and its inhibitor Igf2 receptor (Igf2r) (DeChiara et al., 1991; Lau et al., 1994; Wang et al., 1994). Since then, it has emerged that most imprinted genes modulate fetal growth and resource acquisition in a variety of ways. First, imprinted genes are required for the development of a functional placenta, the organ that mediates the exchange of nutrients between mother and fetus. Second, these genes act in an embryo-autonomous manner to affect the growth rate and organogenesis. Finally, imprinted genes can signal the nutritional status between mother and fetus, and can modulate levels of maternal care. Importantly, many imprinted genes have been shown to affect postnatal growth and energy homeostasis. Given that abnormal birthweight correlates with adverse adult metabolic health, including obesity and cardiovascular disease, it is crucial to understand how the modulation of this dosage-sensitive, epigenetically regulated class of genes can contribute to fetal and postnatal growth, with implications for lifelong health and disease.

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20 YEARS OF LEPTIN: Human disorders of leptin action

Cited by 240 publications

References 55 publications

Replacing SNAP-25b with SNAP-25a expression results in metabolic disease

Replacing SNAP-25b with SNAP-25a expression results in metabolic disease

IMAGING IN ENDOCRINOLOGY: The use of functional MRI to study the endocrinology of appetite

Genomic imprinting, growth and maternal–fetal interactions

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