Resistance to diet-induced obesity is associated with increased proopiomelanocortin mRNA and decreased neuropeptide Y mRNA in the hypothalamus

Bergen, Hugo; Mizuno, Tooru M.; Taylor, J.R.; Mobbs, Charles V.

doi:10.1016/s0006-8993(99)02186-1

Cited by 92 publications

(71 citation statements)

References 23 publications

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“…45 The observed overexpression of POMC in leptin-treated animals under HF diet could be explained by higher leptin action on their receptor and could counteract the effect of HF diet on positive energy balance, in an effort to maintain energy homeostasis. These results are in line with the findings of Bergen et al 46 showing compensatory hypothalamic changes in mRNA expression levels of POMC in A/J mice (resistant to diet-induced obesity) fed with HF diet for 14 weeks. Considering that both NPY and POMC are the main neuropeptides stimulating and inhibiting food intake, respectively, it is interesting to highlight that, in control animals, the NPY/POMC ratio increased as an effect of HF diet feeding, whereas in leptin-treated animals, this ratio decreased significantly; this could help to control food intake and thus body weight in leptin-treated animals under HF diet.…”

Section: Discussionsupporting

confidence: 93%

The intake of physiological doses of leptin during lactation in rats prevents obesity in later life

et al. 2007

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Ciber Fisiopatología obesidad y nutrición (CB06/03) Instituto Salud Carlos III, SpainBackground: There is epidemiological evidence that perinatal nutritional factors may have long-term effects on obesity. Which nutrients or food components are involved in this programming mechanism are unknown. Breast milk contains leptin, a hormone that regulates food intake and energy expenditure, and previous studies in rats have shown that leptin orally administered during lactation exerts anorexigenic effects. Objective: To evaluate whether supplementation with physiological doses of oral leptin during lactation has long-term effects on body weight regulation. Design: A daily oral dose of leptin (equivalent to five times the amount of leptin ingested normally from maternal milk during the suckling period) or the vehicle was given to suckling male rats during lactation. Animals were fed after weaning with a normal fat (NF) or a high-fat (HF) diet. We followed body weight and food intake of animals until the age of 6 months, and measured the size of adipose tissue depots, the thermogenic capacity, the expression of leptin in the stomach and adipose tissues and the expression of two appetite-related peptides (neuropeptide Y (NPY) and proopiomelanocortin (POMC)), leptin receptor (OB-Rb) and suppressor of cytokine signalling 3 (SOCS-3) in the hypothalamus at the age of 6 months. Results: Leptin-treated animals had, in adulthood, lower body weight and fat content and ate fewer calories than their untreated controls. Unlike adipocitary leptin production, adult animals that were leptin-treated during lactation displayed higher gastric leptin production without changes in OB-Rb mRNA levels. In addition, in response to HF diet, leptin-treated animals (contrary to controls) showed lower hypothalamic NPY/POMC mRNA ratio. Hypothalamic OB-Rb mRNA levels decreased in control animals as an effect of HF diet feeding, but remained unchanged in leptin-treated animals; SOCS-3 mRNA levels were lower in leptin-treated animals than in their controls, both under normal or HF diet. Conclusion: The animals that received leptin during lactation become more protected against fat accumulation in adult life and seem to be more sensitive to the short-and long-term regulation of food intake by leptin. Thus, leptin plays an important role in the earlier stages of neonatal life, as a component of breast milk, in the prevention of later obesity.

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Section: Discussionsupporting

confidence: 93%

The intake of physiological doses of leptin during lactation in rats prevents obesity in later life

et al. 2007

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“…Moreover, POMC and CRH increased in relation to adiposity in NPYko mice but fell in DIO wild-type mice. It has previously been reported that DIO in C57Bl/6J mice is associated with elevation of POMC levels in the hypothalamus (32). Our results suggest that the leaner phenotype of NPYko mice is partly mediated by the anorexigenic action of POMC and CRH.…”

Section: Discussionsupporting

confidence: 66%

Neuropeptide Y Deficiency Attenuates Responses to Fasting and High-Fat Diet in Obesity-Prone Mice

Patel

Hawkins

et al. 2006

Diabetes

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Neuropeptide Y (NPY) stimulates feeding and weight gain, but deletion of the NPY gene does not affect food intake and body weight in mice bred on a mixed genetic background. We reasoned that the orexigenic action of NPY would be evident in C57Bl/6J mice susceptible to obesity. NPY deficiency has no significant effect in mice fed a normal rodent diet. However, energy expenditure is elevated during fasting, and hyperphagia and weight gain are blunted during refeeding. Expression of agouti-related peptide (AGRP) in the hypothalamus is increased in NPY knockout (NPYko) than wild-type mice, but unlike wild type there is no further increase in AGRP when NPYko mice are fasted. Moreover, NPYko mice have higher oxygen consumption and uncoupling protein-1 expression in brown adipose tissue during fasting. The failure of an increase in orexigenic peptides and higher thermogenesis may contribute to attenuation of weight gain when NPYko mice are refed. C57Bl/6J mice lacking NPY are also less susceptible to diet-induced obesity (DIO) as a result of reduced feeding and increased energy expenditure. The resistance to DIO in NPYko mice is associated with a reduction in nocturnal feeding and increased expression of anorexigenic hypothalamic peptides. Insulin, leptin, and triglyceride levels increase with adiposity in both wild-type and NPYko mice. Diabetes 55:3091-3098, 2006 E nergy balance involves a complex interaction between hormones, such as leptin, insulin, and glucocorticoids, and key neurons in the hypothalamus, brainstem, and other areas of the central nervous system (1). Neuropeptide Y (NPY) is expressed in the hypothalamus, stimulates food intake, decreases energy expenditure, and increases body weight when administered in the brain (1). Consistent with its role as an orexigenic peptide, hypothalamic NPY expression is increased during fasting and hypoglycemia and suppressed by feeding, leptin, and insulin (1). Despite the strong pharmacological evidence supporting its role in energy balance, genetic disruption of NPY did not affect feeding or body weight in mice bred on a mixed 129J-C57Bl/6J background (2). Paradoxically, deletion of NPY or the Y1 and Y5 receptors that mediate effects of NPY on energy balance resulted in mild obesity (3-6). Nonetheless, loss of NPY attenuated hyperphagia and obesity in Lep ob/ob mice (7). Others have also shown that NPY deficiency decreases hyperphagia after fasting and hypoglycemia (8 -10). Furthermore, deletion of NPY Y2/Y4 receptors prevents diet-induced obesity (DIO) (11).We reasoned that the controversies surrounding the actions of NPY in these genetic models are partly due to the use of the 129 mouse strain, which is resistant to obesity (12). The seemingly normal phenotype of NPYdeficient mice could also result from compensatory developmental changes. For example, ablation of hypothalamic neurons expressing NPY/AGRP did not alter feeding in neonatal mice, whereas ablation in adults caused starvation (13,14). AGRP is coexpressed with NPY in the arcuate nucleus, and both peptides ...

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“…Although high-fat feeding in wild-type mice results in decreased expression of NPY and POMC in the arcuate nucleus, these changes are absent in Y2Y4 double-knockout mice [9]. A protective role for increased POMC expression against diet-induced obesity has also been shown by others [10], and decreases in POMC signaling are seen in genetically obese ob/ob and db/db mice [11].…”

Section: Lee Et Al: Nutrition 24(9): 892--899 2008mentioning

confidence: 68%

Synergistic attenuation of obesity by Y2- and Y4-receptor double knockout in ob/ob mice

et al. 2008

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Objective Neuropeptide Y regulates numerous processes including food intake, body composition, and reproduction by at least five different Y receptors. We previously demonstrated a synergistic interaction between Y2 and Y4 receptors in reducing adiposity in chow-or fat-fed Y2Y4-receptor double-knockout mice. In the present study, we investigated whether this synergy could reduce the massive obesity of leptin-deficient ob/ob mice. MethodsMice with germline deletions of Y2 and Y4 receptors were crossed onto the ob/ob strain. Body weight was measured weekly until 15-18 wk of age before decapitation for collection of trunk blood and tissues. ResultsMale and female Y24ob triple mutants showed highly significant reductions in body weight and white adipose tissue mass compared with ob/ob mice. This reduction in body weight was not evident in Y2ob or Y4ob double mutants, and the effect on adiposity was significantly greater than that seen in Y2ob or Y4ob mice. These changes were associated with significant attenuation of the increased brown adipose tissue mass and small intestinal hypertrophy seen in ob/ob mice and with normalization of the low circulating free thyroxine concentrations seen in female ob/ob mice and the high circulating corticosterone concentrations seen in male ob/ob mice. ConclusionThese data reveal a synergistic interaction between Y2 and Y4 receptors in attenuating the massive obesity of ob/ob mice, possibly mediated by stimulation of thyroid function and inhibition of intestinal nutrient absorption. Dual pharmacologic antagonism of Y2 and Y4 receptors could help people to attain and maintain a healthy weight.

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Resistance to diet-induced obesity is associated with increased proopiomelanocortin mRNA and decreased neuropeptide Y mRNA in the hypothalamus

Cited by 92 publications

References 23 publications

The intake of physiological doses of leptin during lactation in rats prevents obesity in later life

The intake of physiological doses of leptin during lactation in rats prevents obesity in later life

Neuropeptide Y Deficiency Attenuates Responses to Fasting and High-Fat Diet in Obesity-Prone Mice

Synergistic attenuation of obesity by Y2- and Y4-receptor double knockout in ob/ob mice

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