Search

Harrold, Joanne A., Peter S. Widdowson, John C. Clapham, and Gareth Williams. Individual severity of dietary obesity in unselected Wistar rats: relationship with hyperphagia. Am J Physiol Endocrinol Metab 279: E340-E347, 2000.--We investigated the relative importance of overeating, thermogenesis, and uncoupling protein (UCP) expression in determining the severity of obesity in male Wistar rats fed a highly palatable diet. After 2 wk of feeding, body weight did not differ significantly from controls (248 [+ or -] 4 vs. 229 [+ or -] 3 g; P [is greater than] 0.3), but rectal temperature, brown adipose tissue (BAT) mass, UCP3 expression in gastrocnemius muscle, and UCP2 expression in white adipose tissue (WAT) were all elevated in diet-fed animals. In a further study, rats fed a palatable diet for 8 wk exhibited higher energy intake and rectal temperature than controls. Dietary-obese rats were divided into high (427-490 g; n = 8) and low (313-410 g; n = 10) weight gainers. The high gainers ate significantly more than the low gainers, and energy intake was positively correlated with weight gain ([r.sup.2] = 0.72, P [is less than] 0.01). UCP2 and UCP3 mRNA levels in gastrocnemius muscle were significantly increased above lean controls in all diet-fed animals, whereas UCPs in WAT and BAT did not differ significantly from controls. Whereas rats fed palatable food exhibited a thermogenic response, there was no significant difference in core temperature between high and low gain groups (37.5 [+ or -] 0.1 vs. 37.6 [+ or -] 0.1 [degrees] C; P [is greater than] 0.5). We conclude that a higher energy intake is the critical factor determining susceptibility to dietary obesity in unselected Wistar rats. food intake; uncoupling proteins; thermogenesis; palatable diet

The noradrenaline (NA) and serotonin reuptake inhibitor, sibutramine, gives effective weight loss, but full efficacy cannot be attained at approved doses due to cardiovascular side effects. We assessed in rats the contributions of NA and serotonin transporters to sibutramine's hypophagic and cardiovascular effects, and whether selective 5-hydroxytryptamine (5-HT1A) receptor activation could counteract the latter without affecting the former. Food intake was assessed in freely feeding rats and cardiovascular parameters in conscious telemetered rats. Ex vivo radioligand binding was used to estimate brain monoamine transporter occupancy. Sibutramine (1–10 mg/kg p.o.) dose-dependently reduced food intake; however, 10 mg/kg p.o. markedly elevated blood pressure and heart rate. Sibutramine gave greater occupancy of NA than serotonin reuptake sites. Coadministration of the selective 5-HT1A agonist F-11440 (2.5 mg/kg p.o.) attenuated sibutramine-induced hypertension and tachycardia without altering its food intake effects. The selective NA reuptake inhibitors, nisoxetine or reboxetine, did not alter food intake alone, but each reduced food intake when combined with F-11440. These results suggest that sibutramine-induced hypophagic and cardiovascular effects are largely due to increased brain synaptic NA via NA reuptake inhibition, and that 5-HT1A activation can counter the undesirable cardiovascular effects resulting from increased sympathetic activity. Selective NA reuptake inhibitors did not reduce food intake alone but did when combined with 5-HT1A activation. Hence increased synaptic serotonin, via serotonin reuptake inhibition or 5-HT1A activation, together with increased NA, would appear to produce hypophagia. Thus weight loss with minimal cardiovascular risk could be achieved by 5-HT1A activation combined with NA transporter blockade.Obesity (2009) 17 3, 467–473. doi:10.1038/oby.2008.550 [ABSTRACT FROM AUTHOR]

Focuses on a study which investigated the relative importance of overeating, thermogenesis and uncoupling protein (UCP) expression in determining the severity of obesity in male Wistar rats fed a highly palatable diet. Overview of the mechanism of action of UCP; Account of related studies; Methodology and results; Analysis of results.

We have examined the effects of underfeeding and obesity on the density of hypothalamic melanocortin MC3 and MC4 receptors (MC3-R and MC4-R, respectively), which may mediate the hypophagic effects of alpha-melanocyte-stimulating hormone (MSH) in the rat. MC3-R and MC4-R were measured by quantitative autoradiography in brain sections using 125I-labeled Nle4-D-Phe7-alpha-MSH (125I-NDP-MSH) and discriminated by masking MC3-R with excess unlabelled gamma2-MSH. High densities of MC4-R occurred in the ventromedial (VMH) and arcuate (ARC) nuclei, median eminence (ME), and medial habenular nucleus (MHb), with lower densities in the dorsomedial hypothalamus (DMH) and forebrain regions. MC3-R were confined to the VMH, ARC, and MHb. After 10-days of food restriction (14% weight loss), density of MC4-R was significantly increased by 20-65% in the VMH, ARC, ME, and DMH, with no changes elsewhere. Similarly, obese (fa/fa) Zucker rats showed 43-98% increases in MC4-R in the same regions. By contrast, rats with diet-induced obesity (18% heavier than controls) showed significantly decreased binding to MC4-R, especially in the VMH, ARC, and ME. MC3-R showed no significant alterations in any model. We suggest that increased density of MC4-R with food restriction and in obese Zucker rats reflects receptor upregulation secondary to decreased release of alpha-MSH, consistent with increased hunger in these models. Conversely, downregulation of MC4-R in diet-induced obesity may indicate increased alpha-MSH secretion in an attempt to limit overeating. This alpha-MSH/MC4-R system may be inhibited by leptin and/or insulin. MC3-R are not apparently involved in regulating feeding. [ABSTRACT FROM AUTHOR]

Sibutramine (Meridia™) is a serotonin (5-HT)/norepinephrine (NE) reuptake inhibitor approved for the long-term treatment of obesity. Its use is associated with elevations in blood pressure (BP) and heart rate (HR) in some patients, limiting its use as well as the ability to dose titrate upwards to achieve greater efficacy. It was hypothesised that the addition of 5-HT[sub 1A] agonism to monoamine reuptake inhibition would reduce the risk of unwanted cardiovascular activity. We have identified two orally active agents, PSN S1 and PSN S2, that are potent inhibitors of NE reuptake and agonists at 5-HT[sub 1A] receptors in vitro, whilst PSN S2 also exhibits 5-HT reuptake inhibition. PSN S1 and PSN S2 significantly and dose dependently inhibit food intake in lean male SD rats to a similar extent as sibutramine (ED[sub 50] 24h after oral dosing; PSN S1 = 16.7mg/kg; PSN S2 = 3.3mg/kg; sibutramine = 7.5mg/kg). In telemetered male Han-Wistar rats, single doses of PSN S1 and PSN S2 (2 x ED[sub 50] to inhibit food intake at 24h) in contrast to sibutramine (1.3 x ED[sub 50] to inhibit food intake at 24h) caused no significant rise in mean BP [average mean between 2-8h; mmHg; vehicle controls = 103±1; PSN S1 (30mg/kg) = 105±2; PSN S2 (7mg/kg) = 107±2; sibutramine (10mg/kg) = 113±1*; *P<0.0005 versus controls] or HR [average mean between 2-8h; beats/min; vehicle controls = 365±6; PSN S1 = 312±5*; PSN S2 = 377±4; sibutramine = 402±7*; *P<0.001 versus controls]. Daily oral dosing of PSN S1 (11.2mg/kg) and PSN S2 (1.65mg/kg) for 4 weeks to weight stable dietary induced obese (DIO) female Wistar rats significantly reduced food intake and body weights. The body weights of the drug treated animals were reduced by approximately 10% cf controls, matching the weight loss induced by a relatively high dose of sibutramine (5mg/kg) [final body weights (g): vehicle = 431±7; PSN S1 = 390±4*; PSN S2 = 388±3*; sibutramine = 385±7*; *P<0.05 vs controls]. The decreases in body weight induced by PSN S1, PSN S2 and sibutramine were associated with reduced food intake. Carcass analysis confirmed that the weight loss induced by all 3 compounds could be attributed to a specific loss of body fat. In conclusion, PSN S1 and PSN S2 cause equivalent weight loss to sibutramine in rats, but have a superior cardiovascular profile after single doses. Translation of these effects to man would potentially allow dose-escalation to achieve greater weight loss than sibutramine. [ABSTRACT FROM AUTHOR]