Hypothalamic dysfunction in obesity

Abstract

A growing number of studies have shown that a diet high in long chain SFA and/or obesity cause profound changes to the energy balance centres of the hypothalamus which results in the loss of central leptin and insulin sensitivity. Insensitivity to these important anorexigenic messengers of nutritional status perpetuates the development of both obesity and peripheral insulin insensitivity. A high-fat diet induces changes in the hypothalamus that include an increase in markers of oxidative stress, inflammation, endoplasmic reticulum (ER) stress, autophagy defect and changes in the rate of apoptosis and neuronal regeneration. In addition, a number of mechanisms have recently come to light that are important in the hypothalamic control of energy balance, which could play a role in perpetuating the effect of a high-fat diet on hypothalamic dysfunction. These include: reactive oxygen species as an important second messenger, lipid metabolism, autophagy and neuronal and synaptic plasticity. The importance of nutritional activation of the Toll-like receptor 4 and the inhibitor of NF-kB kinase subunit b/NK-kB and c-Jun amino-terminal kinase 1 inflammatory pathways in linking a high-fat diet to obesity and insulin insensitivity via the hypothalamus is now widely recognised. All of the hypothalamic changes induced by a high-fat diet appear to be causally linked and inhibitors of inflammation, ER stress and autophagy defect can prevent or reverse the development of obesity pointing to potential drug targets in the prevention of obesity and metabolic dysfunction.Hypothalamus: Obesity: High-fat diet: Inflammation: Neuronal and synaptic plasticityThe developed world is currently facing an epidemic of obesity. Diseases associated with obesity, particularly type 2 diabetes, CVD, cancer, stroke and mental health issues, including dementia (1,2) are provoking a crisis in health care, adversely affecting health and life expectancy and increasing health care costs, estimated to be up to £45 billion by 2050 in the UK alone (3) . Direct and indirect costs of type 2 diabetes, for example, one of the major health consequences of obesity, are currently £21 . 8 billion and set to rise to £35 . 6 billion by 2035-36 in the UK (4) .Obesity is the result of a disproportionately high energy intake compared to energy expenditure and is a complex interaction between environmental and genetic factors (5) with monogenic defects being relatively rare (6) . It seems obvious that an energy-dense diet, high in saturated fat and sugar, should cause weight gain and increased adiposity; nonetheless it appears that these diets cause a profound change in energy balance that does not result from a simple increase in energetic intake. Diet composition, particularly the presence of long-chain saturated fats, results in metabolic dysfunction and increased adiposity and body weight, Abbreviations: AgRP, agouti-related peptide; ARC, arcuate nuclei; CART, cocaine and amphetamine-regulated transcript; CNTF, ciliary neurotrophic factor; ER, endoplasmic reticulum; I...

Small Molecular Allosteric Activator of the Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA) Attenuates Diabetes and Metabolic Disorders

“…For instance, parallel to the conferred beneficial effects on the liver, we also documented similar bioactivity of CDN1163 in the hearts of ob/ob mice where we observed significant improvement of cardiac performance and mitochondrial function. 3 This is of interest as cardiovascular co-morbidities are common in diabetes, and therefore, it is possible that dual pharmacological activities of SERCA2 agonism may also have beneficial effects on the cardiovascular system by increasing cardiac muscle contractility and improving vascular tone (46 -48).…”

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Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes

“…One particularly intriguing example is the hypothalamus, which functions as a hub that integrates metabolic and hormonal cues to regulate food intake and energy expenditure, thereby modulating lipid metabolism and glucose homeostasis [48,49]. Obesity might induce hypothalamic dysfunction by stimulating inflammation through the inhibitor of κβ (IKKβ)/nuclear factor-κB (NF-κβ) pathway leading to hypothalamic resistance to insulin and the satiety hormone, leptin [50].…”

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