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Symposium Report |
1 Department of Pharmacology, The University of Melbourne, Parkville, Victoria 3010, Australia 2 Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
Abstract
Obesity induced by a high-fat diet was associated with increased tail-cuff blood pressure in adult rats. The mechanisms underlying obesity-related hypertension are unclear, but increased sympathetic activation most probably plays a role. Neuroendocrine alterations observed in obesity may influence both feeding patterns and blood pressure. Work from our laboratory has shown that chronic overfeeding in rats leads to changes in neuropeptide Y (NPY) and 
-melanocyte stimulating hormone (MSH) in the hypothalamus. These peptides have central effects on blood pressure, indicating that obesity-related changes in the CNS may impact on cardiovascular function. Population studies suggest that nutrition in early life can influence the subsequent risk of obesity and high blood pressure. To examine the impact of early postnatal overnutrition on blood pressure and adipose-derived mediators, we adjusted rat litters to 3 or 12 pups (overnutrition and control, respectively). Pups raised in small litters were 15% heavier at weaning, and this intervention was associated with a modest elevation of blood pressure and body weight as adults (16 weeks). Animals raised in small litters had increased 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) mRNA in white adipose tissue as adults, which may impact on cardiovascular function. Adjustment of diet after weaning, to 30% fat diet or standard chow, allowed comparison of the impact of different periods of overnourishment. Implementation of a high-fat diet at weaning overcame the effect of litter size on body weight from 10 weeks of age. Blood pressure rose progressively with high-fat feeding and was positively correlated with leptin and body weight. Chronic consumption of a high-fat diet led to marked increases in leptin and insulin and modest increases in blood pressure, and impacts on brain transmitters implicated in the regulation of both appetite and blood pressure. Overnourishment during early postnatal development led to profound changes in body weight at weaning, which tended to abate with maturation. It also led to long-term changes in some adipose-derived mediators, possibly increasing cardiovascular risk.
(Received 5 June 2005;
accepted after revision 6 July 2005; first published online 16 August 2005)
Corresponding author M. J. Morris: Department of Pharmacology, The University of Melbourne, Victoria 3010, Australia. Email: mjmorris{at}unimelb.edu.au
Cardiovascular impact of obesity
Obesity is a health problem of increasing prevalence in every continent and represents a major public health concern. While many studies indicate that obesity is a major risk factor for cardiovascular morbidity and mortality, the relationship between obesity and hypertension is unclear and could reflect genetic, environmental, hormonal and haemodynamic factors (Redon, 2001).
As discussed in this issue, much interest has focused on the potential role of sympathetic activation in obesity-related hypertension. The sympathetic system adapts to changes in dietary caloric intake, with sympathetic nervous activation and inhibition accompanying caloric excess or deficiency, respectively (Rumantir et al. 1999). Chronic overeating in rodents stimulated the sympathetic nervous system, resulting in elevated blood pressure (Landsberg & Krieger, 1989). While obesity-induced hypertension has been linked to hyperinsulinaemia-induced activation of the sympathetic nervous system (Mikhail et al. 1999), another important contribution to obesity-related hypertension is the adipocyte-derived hormone, leptin, which circulates at levels proportional to fat mass. The actions of leptin are mediated by leptin receptors (Ob-Rb) found predominantly in the hypothalamus, which regulate the production of orexigenic and anorexigenic peptides. Particularly important in the central regulation of feeding is the orexigenic transmitter, neuropeptide Y (NPY), which has potent stimulatory effects on food intake. NPY exerts its major feeding effect in the paraventricular nucleus of the hypothalamus (PVN). In addition to its regulatory effects on feeding, leptin administration can increase sympathetic activity and blood pressure (Shek et al. 1998; Dunbar & Lu, 1999; Rahmouni & Haynes, 2004). Furthermore, leptin may also affect blood pressure by inhibiting NPY synthesis, and we have shown that leptin can reduce NPY release from the hypothalamus and medulla (Lee & Morris, 1998). Microinjections of NPY into the nucleus tractus solitarii (NTS), a medullary region that integrates cardiovascular signals, elicits a dose-dependent fall in blood pressure and heart rate (Morris et al. 1997).
As shown in Fig. 1, other circulating hormones, and mediators produced by adipose tissue, have the potential to regulate blood pressure via the modulation of vascular tone or intravascular volume (Lyon et al. 2003; Rajala & Scherer, 2003; Fruhbeck, 2004). Adipocytokines such as adiponectin, which is decreased in human obesity, interleukin-6 (Il-6) and tumour necrosis factor (TNF-) released from adipose tissue, can contribute to endothelial dysfunction, thereby increasing the risk of atherosclerosis (Lyon et al. 2003). In addition, the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), and angiotensinogen, are expressed by adipose tissue and these may play a key role in the cardiovascular risk associated with visceral obesity. 11ß-HSD1 converts cortisone to its active form, cortisol. Transgenic mice overexpressing 11ß-HSD1 in adipose tissue have hypertension accompanied by visceral fat accumulation, and insulin and leptin resistance (Masuzaki et al. 2003).
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In order to investigate the link between obesity and hypertension our laboratory has developed palatable high-fat diets for rodents that can be applied in young adulthood, allowing us to examine the cardiovascular/metabolic consequences of voluntary overfeeding (Hansen et al. 2001, 2004). Weight-matched (200 g) groups of male rats received standard chow (12% calories as fat) or a highly palatable cafeteria-style diet (consisting of supplemented chow, meat pies, pasta and cakes, 30% calories as fat; Hansen et al. 2004). Animals can be followed for various periods of dietary intervention (Hansen et al. 2001, 2004). Blood pressure measurements by plethysmography, as well as tail vein blood samples, are taken at regular intervals. While body weight, fat mass and plasma leptin increase soon after implementation of the diet (Hansen & Morris, 2002), increases in blood pressure only become apparent after 10 weeks or so. Hypothalamic NPY levels decreased with chronic high-fat feeding and we observed significant negative correlations between total hypothalamic NPY and plasma leptin (Hansen & Morris, 2002).
Childhood obesity
Childhood obesity is also increasing throughout the world (Kohn & Booth, 2003; Slyper, 2004) and demographic data suggest that environmental influences operating early in life are involved. Childhood obesity is associated with subsequent hyperlipidaemia, glucose intolerance and hypertension (Caprio et al. 1996). Many of the cardiovascular consequences that characterize adult obesity are preceded by abnormalities that begin in childhood. Managing childhood obesity and its consequences requires an understanding of the underlying pathophysiological changes of early-onset obesity. In rodents, reducing litter size postnatally increases food availability and is used to study the consequences of early overnutrition (Plagemann et al. 1999). In the following section we describe studies from our laboratory in which we investigated the long-term metabolic and cardiovascular consequences of preweaning overnourishment, which to date have been little examined.
In addition to examining the chronic impact of a short period of overnourishment (using litter adjustment), we have also examined the impact of continuous overnutrition from birth, induced by small litter size followed by a high-fat diet.
Modelling early-onset obesity
Litter adjustment
Methods used to model early-onset overnourishment are shown in Fig. 2. On day 1 of life, rat pup litters were adjusted to 3 (small litter) or 12 male animals (normal litter) of similar body weights, to induce early postnatal overnutrition or normal nutrition, respectively. Animals in the small litters were significantly heavier than those in normal litters by day 14 (41.1 ± 0.8 versus 32.9 ± 0.5 g, P < 0.001). At 24 days of age the pups raised in small litters were 15% heavier than those in normal litters (80.7 ± 1.3 versus 70.0 ± 0.9 g, P < 0.001). This increase in body weight was associated with a 20–30% increase of milk consumption in animals in small litters. Leptin levels were more than doubled at weaning in these animals and remained significantly increased at 8 weeks of age, while animals were consuming low-fat chow (Fig. 3A). At 16 weeks there was no significant difference in plasma leptin (Fig. 3A). When Northern blot analysis for 11ß-HSD1 expression in retroperitoneal white adipose tissue was undertaken at 16 weeks of age, increased 11ß-HSD1 mRNA was observed in rats raised in small litters (Fig. 3B). This suggests that there may be some long-term effects of early-onset overnutrition on 11ß-HSD1, possibly representing a programming effect of early overnutrition.
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Litter adjustment, followed by normal or high-fat diet
In a subsequent study, at weaning (day 24), pups of both litter sizes were divided into groups receiving standard chow (12% calories as fat) or high-fat diet (30% calories as fat; see Fig. 2). Animals raised in small litters were significantly heavier than those in normal litters, regardless of their diet (Fig. 4A; Velkoska et al. 2005). However, from 11 weeks of age there was no significant effect of litter size on body weight (Fig. 4A). Plasma leptin was elevated in animals in small litters compared to those in normal litters at 8 weeks of age, irrespective of their postweaning diet (Fig. 4B), suggesting that early overnourishment has long-lasting effects on body fat. At 16 weeks of age organ weights and fat mass of the animals in small litters tended to be slightly heavier than those from normal litters, but these differences did not reach significance (Velkoska et al. 2005). Again, there was a modest 4–5% litter size-related increase in body weight in both diet groups.
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Diet-related increases in systolic blood pressure appear to be delayed relative to increases in body weight and plasma leptin. While blood pressure was similar in all treatment groups at 7 weeks of age, increases in blood pressure of 11–20 mmHg were evident in both high-fat-fed groups relative to chow-fed controls at 13 weeks (Velkoska et al. 2005). When high-fat and chow diet rats were combined, blood pressure was positively correlated with plasma leptin and with plasma insulin at 13 weeks of age in each litter group (Velkoska et al. 2005). Significant reductions in hypothalamic NPY (including PVN) were observed at 16 weeks in response to the high-fat diet. In addition, a significant negative correlation was apparent between leptin and total hypothalamic NPY in both litter size groups (Velkoska et al. 2005).
Impact of early overnutrition
Although overnutrition in critical periods of development is suggested to confer increased risk of subsequent obesity and metabolic disorders, the relationship between the timing of onset of overeating and the risk of obesity is unclear. In our hands, postnatal overnutrition induced by small litter size led to early changes in body weight, most probably related to increased milk consumption. This impact of small litter size to increase body weight was maintained for a period into young adulthood (10 weeks), in accordance with previous studies (Faust et al. 1980; Plagemann et al. 1999) which showed increased fat mass and fat cell number as a result of early overnutrition. Our work demonstrates the development of marked hyperleptinaemia in the animals in small litters along with the greater body weight gain. It is also possible that early environmental effects related to the alteration in litter size, such as altered mother–pup interaction, may impact on subsequent behaviour and stress response. Earlier work showed that handling of pups led to increased maternal care (licking and grooming), and that this was associated with dampened hypothalmo–pituitary–adrenal responsivity to stress as adults (Liu et al. 1997).
We have also examined the effect of prolonging the early-onset overnourishment by subjecting animals to a high-fat diet postweaning. Regardless of litter size, the high-fat diet resulted in a significant increase in body weight compared to chow diet after only 2 weeks. We observed diet-induced hyperleptinaemia and hyperinsulinaemia, as well as significant increases in fat mass. These findings demonstrate that long-term feeding of a high-fat diet can override early litter size-induced effects, indicating the importance of overnutrition in later life (Velkoska et al. 2005). However, the animals raised in the small litters remained moderately heavier than those raised in normal litters throughout adulthood, although this failed to reach significance. This suggests that early nutrition may still play a small but important role.
What links obesity and blood pressure?
Adjustment of litter size in rats, thereby influencing early feeding patterns, can influence adult blood pressure (Myers et al. 1996; Plagemann et al. 1999), as can the type of diet. We have looked at this question in two ways. First, implementation of a high-fat diet (either as an adult or at weaning) led to early and marked increases in body weight and leptin concentrations; these were associated with modest increases in systolic blood pressure that were manifest after several months. Second, overfeeding rats for a limited period from a very early age (day 1–24) also led to prolonged increases in body weight, and leptin concentrations remained elevated long after a normal diet was implemented postweaning. The effect of short-term overnutrition, induced by reducing litter size, on blood pressure requires further investigation in suitably powered studies.
Early work has shown that high caloric intake can increase sympathetic activity, thus increasing noradrenaline turnover in peripheral tissues and raising resting plasma noradrenaline, resulting in elevated blood pressure (Landsberg & Krieger, 1989). Studies in humans suggest that there may be vascular bed-specific increases in sympathetic activity rather than an overall increased sympathetic drive. Obesity-related increases in blood pressure have been associated with hyperleptinaemia (Rahmouni & Haynes, 2004) and increased sympathetic activity to the interscapular brown adipose tissue (iBAT), kidney and adrenal gland. Recent studies have shown that microinjection of leptin into discrete hypothalamic regions, such as the ventromedial or dorsomedial hypothalamus, led to differential effects on sympathetic vasomotor tone (Marsh et al. 2003), suggesting that sympathetic activation due to leptin is mediated via the central nervous system. Other observations support this suggestion, since lesion of the arcuate nucleus abolished the sympathetic response to leptin infusion (Haynes, 2000). In contrast, injections of NPY into the third ventricle or the PVN results in decreased sympathetic activity to iBAT (Egawa et al. 1991). The potential contribution to altered cardiovascular control of the reduction in hypothalamic NPY that we consistently observe in chronic dietary obesity is unknown, and warrants investigation.
Another important consideration is the distribution of the adipose tissue in obese subjects. Central obesity was shown to be associated with greater sympathetic activation relative to peripheral obesity, with equivalent impairment in baroreflex control (Grassi et al. 2004). Another report found no elevation in muscle sympathetic nerve activity in men with subcutaneous obesity (Alvarez et al. 2004) despite elevated leptin concentrations. The mechanism whereby regional fat deposition confers different cardiovascular risk is intriguing. In a previous study we observed increased mRNA levels of 11ß-HSD1 in retroperitoneal white adipose tissue in adult rats that were overnourished as young pups (Velkoska et al. 2005). It has been speculated that increased glucocorticoid production as a result of increased 11ß-HSD1 mRNA in adipose tissue in obese humans may influence fat accumulation (Rask et al. 2002).
Children who have higher body mass are more likely to become obese adults and are at higher risk of developing cardiovascular disturbances (Gunnell et al. 1998; Jeffreys et al. 2003). Rats overfed from an early age developed increases in body weight, along with changes in the mediators involved in the both the regulation of feeding and blood pressure. Further research is required to increase our understanding of the mechanisms underlying the development of increased blood pressure in obesity.
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Acknowledgements
This work was supported by a Postgraduate Scholarship from the National Heart Foundation of Australia (E.V.) and a Project Grant from the National Health and Medical Research Council, Australia (M.J.M.).
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) and small litters (
) fed chow 
) and small litter high-fat fed (SF n
= 10; •). Data were analysed by two-way ANOVA with repeated measures followed by post hoc least significant difference test. B, plasma leptin concentrations up to 16 weeks of age in NC (open bar), SC (lightly shaded bar), NF (darker shaded bar) and SF (filled bar). Data were analysed with two-way ANOVA followed by post hoc Bonferroni test. Results are expressed as means ±
S.E.M.
P < 0.05, significant difference between litter groups; *P < 0.05, ***P < 0.001 significant difference within litter groups (i.e. diet effect). Adapted from