Abstract
ObjectiveCentral neuropeptide Y (NPY) administration stimulates food intake in rodents. In addition, acute modulation of central NPY signaling increases hepatic production of very low-density lipoprotein (VLDL)-triglyceride (TG) in rats. As hypertriglyceridemia is an important risk factor for atherosclerosis, for which well-established mouse models are available, we set out to validate the effect of NPY on hepatic VLDL-TG production in mice, to ultimately investigate whether NPY, by increasing VLDL production, contributes to the development of atherosclerosis.Research Design and MethodsMale C57Bl/6J mice received an intracerebroventricular (i.c.v.) cannula into the lateral (LV) or third (3V) ventricle of the brain. One week later, after a 4 h fast, the animals received an intravenous (i.v.) injection of Tran35S (100 µCi) followed by tyloxapol (500 mg/kg body weight; BW), enabling the study of hepatic VLDL-apoB and VLDL-TG production, respectively. Immediately after the i.v. injection of tyloxapol, the animals received either an i.c.v. injection of NPY (0.2 mg/kg BW in artificial cerebrospinal fluid; aCSF), synthetic Y1 receptor antagonist GR231118 (0.5 mg/kg BW in aCSF) or vehicle (aCSF), or an i.v. injection of PYY3–36 (0.5 mg/kg BW in PBS) or vehicle (PBS).ResultsAdministration of NPY into both the LV and 3V increased food intake within one hour after injection (+164%, p<0.001 and +367%, p<0.001, respectively). NPY administration neither in the LV nor in the 3V affected hepatic VLDL-TG or VLDL-apoB production. Likewise, antagonizing central NPY signaling by either PYY3–36 or GR231118 administration did not affect hepatic VLDL production.ConclusionIn mice, as opposed to rats, acute central administration of NPY increases food intake without affecting hepatic VLDL production. These results are of great significance when extrapolating findings on the central regulation of hepatic VLDL production between species.
Highlights
The metabolic syndrome is referred to as a cluster of physiological abnormalities correlated with obesity and type 2 diabetes mellitus [1]
In mice, as opposed to rats, acute central administration of neuropeptide Y (NPY) increases food intake without affecting hepatic very low-density lipoprotein (VLDL) production. These results are of great significance when extrapolating findings on the central regulation of hepatic VLDL production between species
To verify that central administration of NPY stimulates food intake, both basal and NPY-induced food intake were assessed during two hours, starting at 09:00 a.m. with all mice serving as their own control
Summary
The metabolic syndrome is referred to as a cluster of physiological abnormalities correlated with obesity and type 2 diabetes mellitus [1]. Hallmarked by insulin resistance, hyperglycemia, hypertension, low high-density lipoprotein-cholesterol (HDL-C) and elevated very low-density lipoprotein-triglyceride (VLDL-TG) levels, this cluster of cardiometabolic risk factors is a strong risk factor for type 2 diabetes and cardiovascular disease [1,2]. Two major neuronal populations within the hypothalamic arcuate nucleus (ARC) exert opposing effects on energy intake. Proopiomelanocortin (POMC) neurons are activated upon food intake to exert anorectic effects by inhibiting food intake and promoting a negative energy balance. When energy levels are low, neuropeptide Y (NPY)/Agouti-related peptide (AgRP) neurons are activated to stimulate food intake and promoting a positive energy balance [5,6,7]
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