Hypothalamic Neuropeptide Y (NPY) Controls Hepatic VLDL-Triglyceride Secretion in Rats via the Sympathetic Nervous System

Bruinstroop, Eveline; Pei, Lei; Ackermans, Mariëtte T.; Foppen, Ewout; Borgers, Anke J; Kwakkel, Joan; Alkemade, Anneke; Fliers, Eric; Kalsbeek, Andries

doi:10.2337/db11-1142

Cited by 74 publications

(86 citation statements)

References 44 publications

(59 reference statements)

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“…Of interest, this reduction in VLDL-TG secretion was observed in 19 h-fasted rats but not in postprandial, 4 h-fasted rats. These results indicate that the SNS is involved in regulating hepatic VLDL-TG secretion specifi cally during fasting, a situation in which lipids become the key substrate for energy metabolism ( 28 ).…”

Section: Anatomy Of Hypothalamic Sympathetic Outflowmentioning

confidence: 91%

“…Central NPY administration increased hepatic expression of lipogenic genes and VLDL-TG production in rats ( 29 ), an effect found to be largely abolished by hepatic sympathetic denervation ( 28 ). Likewise, NPY attenuated the suppression of hepatic VLDL-TG production by insulin in mice, as determined under hyperinsulinemic-euglycemic clamp conditions ( 30 ).…”

Section: Anatomy Of Hypothalamic Sympathetic Outflowmentioning

confidence: 99%

“…In addition, in vitro activation reduced incorporation of exogenously administered fatty acids into the plasma VLDL-TG fraction ( 27 ), pointing to decreased VLDL-TG secretion. Accordingly, Bruinstroop et al ( 28 ) recently showed that hepatic sympathetic denervation in rats reduced hepatic VLDL-TG secretion. Of interest, this reduction in VLDL-TG secretion was observed in 19 h-fasted rats but not in postprandial, 4 h-fasted rats.…”

Section: Anatomy Of Hypothalamic Sympathetic Outflowmentioning

confidence: 99%

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Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies

Geerling

Boon

Kooijman

et al. 2014

Journal of Lipid Research

105

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Dyslipidemia is one of the classical risk factors for cardiovascular diseases (CVD) besides hypertension, type 2 diabetes, and smoking ( 1 ). Dyslipidemia is defi ned as an elevation of plasma LDL-cholesterol (LDL-C), triglycerides (TG), or both, with or without a lowering of HDLcholesterol (HDL-C) ( 2 ). Whereas elevated LDL-C is a well-established major predictor of CVD and has been the primary target for lipid-lowering strategies, evidence suggests that an elevated TG level is an independent risk factor for CVD development as well ( 3, 4 ). Plasma TG levels are considered elevated when they exceed 150 mg/dl, which is observed in 31% of the adult US population ( 5 ). Although hypertriglyceridemia can be caused by rare monogenic disorders, it is mostly caused by a complex interaction between environmental factors and subtle variations in genes involved in lipoprotein metabolism ( 5 ). Current treatments for hypertriglyceridemia are aimed at either increasing TG clearance (e.g., fi brates) ( 6 ) or at decreasing lipolysis in WAT (e.g., niacin) ( 7 ). In addition, reduction of VLDL-TG production lowers plasma TG levels (e.g., exendin-4) ( 8 ).In recent years, the autonomic nervous system, which consists of a sympathetic and a parasympathetic branch, emerged as an important regulator of metabolic homeostasis. Whereas the role of the sympathetic nervous system (SNS) in the regulation of glucose metabolism has been fi rmly established (for review, see Ref. 9 ), considerably fewer studies have focused on its role in TG metabolism. This review provides an update specifi cally on the role of Abstract Important players in triglyceride (TG) metabolism include the liver (production), white adipose tissue (WAT) (storage), heart and skeletal muscle (combustion to generate ATP), and brown adipose tissue (BAT) (combustion toward heat), the collective action of which determine plasma TG levels. Interestingly, recent evidence points to a prominent role of the hypothalamus in TG metabolism through innervating the liver, WAT, and BAT mainly via sympathetic branches of the autonomic nervous system. Here, we review the recent fi ndings in the area of sympathetic control of TG metabolism. Various neuronal populations, such as neuropeptide Y (NPY)-expressing neurons and melanocortin-expressing neurons, as well as peripherally produced hormones (i.e., GLP-1, leptin, and insulin), modulate sympathetic outfl ow from the hypothalamus toward target organs and thereby infl uence peripheral TG metabolism. We conclude that sympathetic stimulation in general increases lipolysis in WAT, enhances VLDL-TG production by the liver, and increases the activity of BAT with respect to lipolysis of TG, followed by combustion of fatty acids toward heat. Moreover, the increased knowledge about the involvement of the neuroendocrine system in TG metabolism presented in this review offers new therapeutic options to fi ght hypertriglyceridemia by specifi cally modulating sympathetic nervous system outfl ow toward liver, BAT, or WAT .-Geerling, J. J., M. R. B...

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Section: Anatomy Of Hypothalamic Sympathetic Outflowmentioning

confidence: 91%

Section: Anatomy Of Hypothalamic Sympathetic Outflowmentioning

confidence: 99%

Section: Anatomy Of Hypothalamic Sympathetic Outflowmentioning

confidence: 99%

See 1 more Smart Citation

Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies

Geerling

Boon

Kooijman

et al. 2014

Journal of Lipid Research

105

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“…The hypothalamus not only regulates food intake and energy expenditure but also the utilisation and partitioning of nutrients (13) , the regulation of glucose homoeostasis (14) and peripheral lipid metabolism (15)(16)(17) . Two important anorexigenic hormones that signal adiposity and nutritional status to the hypothalamus and inhibit food intake are leptin, produced by white adipose tissue (WAT), and insulin, produced by the pancreatic b-cells.…”

Section: Proceedings Of the Nutrition Societymentioning

confidence: 99%

Hypothalamic dysfunction in obesity

Williams

2012

Proc. Nutr. Soc.

112

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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...

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“…Hypothalamic neuropeptide Y infusion augments VLDL-TG secretion 23,24 and impairs the ability of insulin to inhibit VLDL-TG secretion 25 . In contrast, glucose sensing in the mediobasal hypothalamus (MBH) 26 and glycine in the dorsal vagal complex (DVC) 27 suppress hepatic secretion of VLDL-TG.…”

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confidence: 99%

A fatty acid-dependent hypothalamic–DVC neurocircuitry that regulates hepatic secretion of triglyceride-rich lipoproteins

et al. 2015

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The brain emerges as a regulator of hepatic triglyceride-rich very-low-density lipoproteins (VLDL-TG). The neurocircuitry involved as well as the ability of fatty acids to trigger a neuronal network to regulate VLDL-TG remain unknown. Here we demonstrate that infusion of oleic acid into the mediobasal hypothalamus (MBH) activates a MBH PKC-d-K ATP -channel signalling axis to suppress VLDL-TG secretion in rats. Both NMDA receptor-mediated transmissions in the dorsal vagal complex (DVC) and hepatic innervation are required for lowering VLDL-TG, illustrating a MBH-DVC-hepatic vagal neurocircuitry that mediates MBH fatty acid sensing. High-fat diet (HFD)-feeding elevates plasma TG and VLDL-TG secretion and abolishes MBH oleic acid sensing to lower VLDL-TG. Importantly, HFD-induced dysregulation is restored with direct activation of either MBH PKC-d or K ATP -channels via the hepatic vagus. Thus, targeting a fatty acid sensing-dependent hypothalamic-DVC neurocircuitry may have therapeutic potential to lower hepatic VLDL-TG and restore lipid homeostasis in obesity and diabetes.

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Hypothalamic Neuropeptide Y (NPY) Controls Hepatic VLDL-Triglyceride Secretion in Rats via the Sympathetic Nervous System

Cited by 74 publications

References 44 publications

Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies

Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies

Hypothalamic dysfunction in obesity

A fatty acid-dependent hypothalamic–DVC neurocircuitry that regulates hepatic secretion of triglyceride-rich lipoproteins

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