Inhibition of Food Response to Intracerebroventricular Injection of Leptin Is Attenuated in Rats With Diet-Induced Obesity

Abstract

The fat-derived hormone, leptin, is thought to regulate adipose tissue mass by acting on the brain to reduce food intake and increase thermogenesis. We have produced obesity in rats more than 8 weeks old by feeding a high-calorie diet and have then examined the inhibitory effect of intracerebroventricularly injected recombinant murine leptin on their food intake versus control rats. In control rats, randomized injections of leptin (0.5, 2.0, or 10.0 microg) or sterile saline vehicle into the lateral ventricle produced a dose-dependent reduction in normal laboratory diet consumed 1, 4, and 24 h after the lights were turned off. However, in diet-induced obesity, the dose-dependent inhibition of food intake was observed at 1 h only, and the effect was attenuated. Switching the diet-induced obese rats to a normal laboratory diet 1 week before injections of leptin were commenced resulted in a reduction in the daily food consumption. These data suggest that rats made obese by feeding a high-calorie diet override the normal satiety effects of leptin since when they are returned to a normal laboratory diet, they reduce their calorie intake, possibly as a result of a restoration of the satiety effects of endogenous leptin. However, the fact that the hypophagic response to exogenous leptin is impaired in these rats at this time suggests some residual impairment of the satiety signal, perhaps caused by reduced receptor sensitivity and/or near total occupation of receptors by endogenous leptin molecules, levels of which are raised in plasma.

Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

“…Diet-induced obesity in rodents is associated with elevated leptin levels [16] and such rats have apparent leptin resistance [3,4,17]. Identifying whether leptin resistance contributes to or is simply secondary to obesity is important in understanding the mechanisms underlying obesity.…”

“…Treatment by central rAAV-leptin delivery, which leads to both reduced signalling capacity and leptin resistance, exacerbates diet-induced obesity. Leptin resistance is the trademark of diet-induced obesity in rodents [3,4,17] and is generally considered a consequence rather than a cause of obesity. This simple view seems to be at odds with a recent study in transgenic mice overexpressing leptin [26].…”

“…Most obese humans and rodents have elevated serum leptin and impaired physiological responses to exogenously administered leptin, and are hence considered leptin-resistant [1][2][3][4][5]. In contrast, in lean rodents leptin evokes potent anorectic and thermogenic responses and produces marked lipopenia and weight reduction [6][7][8].…”

Long-term food restriction prevents ageing-associated central leptin resistance in wistar rats

“…These rats also show increased serum leptin concentrations during ageing, suggesting that they are leptin resistant [7]. Central leptin resistance has been reported in diet-induced obese [16] but not in old Wistar rats. The fact that old Wistar rats show a decreased uptake of leptin in hypothalamic nuclei with a lower expression of leptin receptor [7], suggest that these rats are also candidates for central leptin resistance associated with ageing.…”

Serotonin controlling feeding and satiety

“…It has been suggested that serotonergic neurons of the dorsal raphe can uptake leptin following its intracerebroventricular administration [271]. The physiological relevance of this finding needs to be determined, though, as pharmacological studies into the hypophagic effects of centrally administered leptin gave inconsistent results [272][273][274][275][276]. Leptin receptor immunoreactivity has also been identified in ascending 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 21 serotonergic neurons [277].…”