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.
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.
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.
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.
A Mutation in the Thyroid Hormone Receptor Alpha Gene Bochukova, Elena; Schoenmakers, Nadia; Schoenmakers, Erik ...
New England journal of medicine/The New England journal of medicine,
01/2012, Letnik:
366, Številka:
3
Journal Article
Recenzirano
Odprti dostop
On whole-exome sequencing, a child with clinical hypothyroidism but borderline-abnormal thyroid hormone levels was found to have a heterozygous nonsense mutation in THRα, encoding a mutant protein ...inhibiting wild-type receptor action in a dominant negative manner.
Thyroid hormones have diverse actions, which include regulation of skeletal growth, maturation of the central nervous system, cardiac and gastrointestinal function, and energy homeostasis. In addition, thyroid hormones control their own production by feedback inhibition of hypothalamic thyrotropin-releasing hormone and pituitary thyroid-stimulating hormone, which direct their synthesis or release. These physiological effects are principally mediated by hormone action through nuclear receptor proteins that act as ligand-inducible transcription factors and either positively or negatively regulate the expression of target genes in different tissues in a hormone-dependent manner.
The receptors are encoded by two genes (
THRA
and
THRB
), each of . . .
Obesity causes significant morbidity and mortality globally. Research in the last three decades has delivered a step-change in our understanding of the fundamental mechanisms that regulate energy ...homeostasis, building on foundational discoveries in mouse models of metabolic disease. However, not all findings made in rodents have translated to humans, hampering drug discovery in this field. Here, we review how studies in mice and humans have informed our current framework for understanding energy homeostasis, discuss their challenges and limitations, and offer a perspective on how human studies may play an increasingly important role in the discovery of disease mechanisms and identification of therapeutic targets in the future.
This Review delves into metabolic disease research performed in mouse models and humans and highlights the challenges in translating research into clinically actionable findings. The discussion includes energy homeostasis, gene-environment interactions, nutritional programming, energy intake and expenditure, and systemic influences on metabolism.
This study shows that the prevalence of hypertension in subjects carrying a loss-of-function mutation in
MC4R
is less than that in overweight or obese control subjects. Metabolic measurements and ...results of a clinical trial testing an MC4R agonist suggest that melanocortinergic signaling influences blood pressure through an insulin-independent mechanism.
This study shows that the prevalence of hypertension in subjects carrying a loss-of-function mutation in
MC4R
is less than that in overweight or obese control subjects. Metabolic measurements and results of a clinical trial testing an MC4R agonist suggest that melanocortinergic signaling influences blood pressure through an insulin-independent mechanism.
Epidemiologic and physiological studies have consistently demonstrated that obesity is a major cause of hypertension.
1
,
2
Studies of rodents with diet-induced obesity suggest that increased activation of the sympathetic nervous system is an important mediator of obesity-induced hypertension: alpha- and beta-adrenergic receptor antagonists and renal denervation significantly blunt the rise in arterial pressure associated with weight gain.
3
–
5
However, the physiological mechanisms linking the development of obesity and hypertension are unclear.
The hypothalamic leptin–melanocortin pathway is critically involved in the control of energy balance, and genetic disruption of molecules in this pathway leads to severe obesity in rodents and humans. . . .
Genetics of Obesity in Humans Farooqi, I. Sadaf; O’Rahilly, Stephen
Endocrine reviews,
2006-December, Letnik:
27, Številka:
7
Journal Article
Recenzirano
Odprti dostop
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.
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