Neuropeptide Y in hypothalamic paraventricular nucleus: a center coordinating energy metabolism. Am. J. Physiol. 266 (Regulatory Integrative Comp. Physiol. 35): R1765-R1770, 1994.-Intracerebroventricular injection of neuropeptide Y (NPY) has two effects on energy metabolism in addition to increased feeding: decreased brown fat thermogenesis and increased white fat lipoprotein lipase (LPL) enzymatic activity. We hypothesized that the paraventricular nucleus (PVN) of the hypothalamus is the

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... lling neural site for these responses. We further hypothesized that NPY stimulation at PVN would reduce gene expression for the critical brown fat thermogenic protein, uncoupling protein (UCP), and increase gene expression for the key white fat storage enzyme, LPL. In the first experiment, three groups of rats received injections every 6 h for 24 h (5 injections total) into the PVN: 1) NPY (1 pg/ 1~1 injection) and ad libitum food; 2) NPY (1 pg/l ~1 injection) and food restricted to control intake; 3) saline injection (1 ~1) and ad libitum food. Both NPY-treated groups showed significant reductions (P < 0.05) in brown fat UCP mRNA levels and marked stimulation of LPL mRNA levels relative to controls. In the second experiment, four groups of seven rats had NPY injected into the PVN: 0 (vehicle control); 0.1 kg; 0.5 kg; and 1 pg. Injections were made every 6 h for 24 h. There was a dose-related reduction. in UCP mRNA produced by the NPY treatment. NPY treatment increased LPL mRNA, but a smooth dosing effect was not evident. The observation that NPY in the PVN can coordinate more than one component of energy metabolism is significant when considered with many reports of responsiveness of NPY activity in the arcuate nucleus-PVN neural circuit to perturbations of energy balance such as fasting and feeding, diabetes, and genetic obesity. Taken together, the observations suggest the presence of a highly organized and comprehensive control element for energy metabolism that reaches far beyond simple appetite control. thermogenesis; energy expenditure; neuropeptides; appetite; food intake THERE IS LITTLE DOUBT that the central nervous system is an important regulator of feeding. There is also strong evidence that portions of energy metabolism, including most obviously energy expended by physical activity, can be regulated by the central nervous system (6). The central regulatory mechanisms for these two sides of energy balance are little understood but have traditionally been thought of as separate functions. Debate about whether perturbations in energy balance, such as obesity, are consequent to a defect in appetite or a defect in energy expenditure is commonplace. Yet there is evidence, from hypothalamic lesioning studies and from direct stimulation of several brain sites, that energy intake and energy expenditure may be coregulated (5, 7, 32). For example, ventromedial hypothalamic lesions produce dramatic increases in food intake but also reduce energy expenditure (30). In considering brain regulation of energy metabolism, much of the focus has been on the rat hypothalamus. Recently, the possible role of peptide neurotransmitters in hypothalamic regulation has been explored. Considerable evidence now supports the role of neuropeptide Y (NPY) in stimulating feeding within the hypothalamus (10,20,27). Ad ministration of NPY into the cerebroventricular system robustly stimulates feeding (20) and is the most potent known neural stimulus for feeding. Localization studies have indicated that the NPY effect on feeding occurs most prominently in the paraventricular nucleus (PVN) of the hypothalamus (26) or in the nearby perifornical area (28). Large concentrations of NPY are normally found at the PVN (9>, and it is known that the PVN receives NPY bearing axonal projections from the arcuate nucleus (2, 9) and other brain sites. The highest concentrations of NPY mRNA expression are also found in the arcuate nucleus of hypothalamus (2 1). Recent evidence indicates that NPY concentrations in the PVN (24), NPY release at the PVN (16), and NPY mRNA levels in the arcuate nucleus (4) increase in response to food deprivation and subsequently normalize when food is provided. We have previously found evidence that intracerebroventricular injection of NPY had two effects in addition to increased feeding (3): NPY independently decreased brown fat thermogenesis [uncoupling protein (UCP) functional activity as assessed by GDP binding] and increased white fat lipoprotein lipase (LPL) enzymatic activity. In unpublished data, we had also found that NPY given intracerebroventricularly reduced brown fat gene expression for the UCP and increased white fat gene expression for LPL. We hypothesized that the PVN of the hypothalamus is the controlling neural site for these responses. We further hypothesized that NPY stimulation would reduce gene expression for the critical brown fat thermogenic protein, UCP, and increase gene expression for the key white fat storage enzyme, LPL.