An increasingly influential perspective conceptualizes both obesity and overeating as a food addiction accompanied by corresponding brain changes. Because there are far-reaching implications for ...clinical practice and social policy if it becomes widely accepted, a critical evaluation of this model is important. We examine the current evidence for the link between addiction and obesity, identifying several fundamental shortcomings in the model, as well as weaknesses and inconsistencies in the empirical support for it from human neuroscientific research.
The identification of the hormone leptin by Friedman et al (1) in 1994 has proved to be a seminal observation in biomedical science. The discovery that a circulating protein secreted almost ...exclusively by adipocytes could regulate body weight through its effects on food intake and energy expenditure represented a remarkable breakthrough in our understanding of the molecular components of the systems involved in energy homeostasis. In this article, we describe how the identification of humans with mutations in the gene encoding leptin and the characterization of the associated clinical phenotype of congenital leptin deficiency, which includes hyperphagia, severe obesity, hypogonadism, and impaired immunity, has provided insights into the role of leptin-responsive pathways in the regulation of eating behavior, intermediary metabolism, and the onset of puberty. We and others have also been able to demonstrate that leptin signaling plays a critical role in the regulation of reproductive and immune function in humans, which places leptin at the center of the complex networks that coordinate changes in nutritional state with many diverse aspects of mammalian biology.
Neuronal circuits within the hypothalamus play a critical role in the homeostatic regulation of body weight. By disrupting the development or function of these circuits, human monogenic disorders ...cause hyperphagia (increased food intake), neuroendocrine abnormalities, impaired sympathetic nervous system activation, and obesity. Some genetic disorders also cause maladaptive behaviors such as anxiety, autism, emotional lability, and aggression, highlighting the role of the specific molecules expressed by these hypothalamic neurons in the regulation of innate behaviors that are essential to survival. These findings inform understanding of a wide range of clinical disorders and highlight the challenges associated with targeting these hypothalamic pathways for weight loss therapy.
The global rise in the prevalence of obesity and associated co-morbidities such as type 2 diabetes, cardiovascular disease, and cancer represents a major public health concern. The biological ...response to increased consumption of palatable foods or a reduction in energy expenditure is highly variable between individuals. A more detailed mechanistic understanding of the molecular, physiological, and behavioral pathways involved in the development of obesity in susceptible individuals is critical for identifying effective mechanism-based preventative and therapeutic interventions.
Understanding the pathways involved in the susceptibility and development of obesity is critical for identifying effective preventative and therapeutic interventions.
FTO is a nuclear protein belonging to the AlkB-related non-haem iron- and 2-oxoglutarate-dependent dioxygenase family. Although polymorphisms within the first intron of the FTO gene have been ...associated with obesity, the physiological role of FTO remains unknown. Here we show that a R316Q mutation, inactivating FTO enzymatic activity, is responsible for an autosomal-recessive lethal syndrome. Cultured skin fibroblasts from affected subjects showed impaired proliferation and accelerated senescence. These findings indicate that FTO is essential for normal development of the central nervous and cardiovascular systems in human and establish that a mutation in a human member of the AlkB-related dioxygenase family results in a severe polymalformation syndrome.
Thyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 and TRβ2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental ...retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using whole-exome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TRα-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues.
Weight gain and weight loss are associated with changes in blood pressure through unknown mechanisms. Central melanocortinergic signaling is implicated in the control of energy balance and blood ...pressure in rodents, but there is no information regarding such an association with blood pressure in humans.
We assessed blood pressure, heart rate, and urinary catecholamines in overweight or obese subjects with a loss-of-function mutation in MC4R, the gene encoding the melanocortin 4 receptor, and in equally overweight control subjects. We also examined the effects of an MC4R agonist administered for 7 days in 28 overweight or obese volunteers.
The prevalence of hypertension was markedly lower in the MC4R-deficient subjects than in the control subjects (24% vs. 53%, P=0.009). After the exclusion of subjects taking antihypertensive medications, blood-pressure levels were significantly lower in MC4R-deficient subjects than in control subjects, with mean (+/-SE) systolic blood pressures of 123+/-14 mm Hg and 131+/-12 mm Hg, respectively (P=0.02), and mean diastolic blood pressures of 73+/-10 mm Hg and 79+/-7 mm Hg, respectively (P=0.03). As compared with control subjects, MC4R-deficient subjects had a lower increase in heart rate on waking (P=0.007), a lower heart rate during euglycemic hyperinsulinemia (P<0.001), and lower 24-hour urinary norepinephrine excretion (P=0.04). The maximum tolerated daily dose of 1.0 mg of the MC4R agonist led to significant increases of 9.3+/-1.9 mm Hg in systolic blood pressure and of 6.6+/-1.1 mm Hg in diastolic blood pressure (P<0.001 for both comparisons) at 24 hours, as compared with placebo. Differences in blood pressure were not explained by changes in insulin levels; there were no significant adverse events.
Results of our genetic and pharmacologic studies implicate melanocortinergic signaling in the control of human blood pressure through an insulin-independent mechanism.
Genetics of Obesity in Humans Farooqi, I. Sadaf; O’Rahilly, Stephen
Endocrine reviews,
2006-December, Volume:
27, Issue:
7
Journal Article
Peer reviewed
Open access
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.
Obesity and its associated comorbidities represent one of the biggest public health challenges facing the world today. The heritability of body weight is high, and genetic variation plays a major ...role in determining the interindividual differences in susceptibility or resistance to the obesogenic environment. Here we discuss how genetic studies in humans have contributed to our understanding of the central pathways that govern energy homeostasis. We discuss how the arrival of technological advances such as next-generation sequencing will result in a major acceleration in the pace of gene discovery. The study of patients harboring these genetic variants has informed our understanding of the molecular and physiological pathways involved in energy homeostasis. We anticipate that future studies will provide the framework for the development of a more rational targeted approach to the prevention and treatment of genetically susceptible individuals.
Neural circuits in the hypothalamus play a key role in the regulation of human energy homeostasis. A critical circuit involves leptin-responsive neurons in the hypothalamic arcuate nucleus (the ...infundibular nucleus in humans) expressing the appetite-suppressing neuropeptide proopiomelanocortin (POMC) and the appetite-stimulating Agouti-related peptide. In the fed state, the POMC-derived melanocortin peptide α-melanocyte-stimulating hormone stimulates melanocortin-4 receptors (MC4Rs) expressed on second-order neurons in the paraventricular nucleus of the hypothalamus (PVN). Agonism of MC4R leads to reduced food intake and increased energy expenditure. Disruption of this hypothalamic circuit by inherited mutations in the genes encoding leptin, the leptin receptor, POMC, and MC4R can lead to severe obesity in humans. The characterization of these and closely related genetic obesity syndromes has informed our understanding of the neural pathways by which leptin regulates energy balance, neuroendocrine function, and the autonomic nervous system. A broader understanding of these neural and molecular mechanisms has paved the way for effective mechanism-based therapies for patients whose severe obesity is driven by disruption of these pathways.
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