Effects of a High‐Fat Diet and Strain on Hypothalamic Gene Expression in Rats

Schaffhauser, Andrea O.; Madiehe, Abram Madimabe; Braymer, Hugh D.; Bray, George A.; York, David A.

doi:10.1038/oby.2002.161

Cited by 45 publications

(29 citation statements)

References 60 publications

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“…HTR2C density and mRNA have been found to increase in the hypothalamus of mice on high-fat diets (Huang et al 2004), in response to low 5-HT concentrations in the ventromedial hypothalamus nucleus (VHM). Increases in leptin but a reduction in HTR2C mRNA in the hypothalamus have also been observed in high-fat diets (Schaffhauser et al 2002). In rats, leptininduced anorexia and milk intake was attenuated by the HTR2C antagonists SB242084 and SB206553, respectively (von Meyenburg et al 2003;Yamada et al 2003).…”

Section: Discussionmentioning

confidence: 93%

Complex HTR2C linkage disequilibrium and promoter associations with body mass index and serum leptin

et al. 2005

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The occurrence of obesity, eating disorders, and related diseases has increased in many parts of the world. Given that few strong genetic factors have been found, it is clear that these are complex multi-factorial diseases. The serotonin receptor 2C, a member of the 5-HTergic system, has been implicated in the control of phagia and obesity. We report a detailed investigation of linkage disequilibrium (LD) within and between the HTR2C promoter and the flanking sequences around a commonly utilized marker in the second coding exon of HTR2C. We suggest that inconsistent associations between HTR2C and several phenotypes, including obesity, may be due to the LD pattern across the gene in which recombination and gene conversion have been influential. The nucleotide and haplotype distribution is consistent with that of the neutral mutation model. The number of haplotypes suggests demographic influences or over dominant selection that may have a function in HTR2C expression. Using the fine LD pattern, we describe a possible association with promoter haplotypes and diplotypes, including a GT microsatellite, and body mass index (BMI) > or =30 kgm(-2) (P<0.0001). SNP -995G>A heterozygotes, as well as promoter diplotypes, were found to marginally influence higher serum leptin corrected for percentage body fat (P=0.01), which might suggest that these subjects are leptin resistant. Our results complement previous studies of HTR2C in both mice and humans, and suggest the importance of genetic variation and elucidating the fine LD structure in uncovering the genetic factors of obesity.

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Section: Discussionmentioning

confidence: 93%

Complex HTR2C linkage disequilibrium and promoter associations with body mass index and serum leptin

et al. 2005

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“…The Osborne-Mendel rat is one of these DIO-S rats. Its NPY mRNA expression is about 50% higher than in S5B/P1 rats (Schaffhauser et al 2002). Despite this increase, Y1 and Y5 mRNA expression is raised by 16-71% with the highest augmentation measured on a LF diet (Schaffhauser et al 2002).…”

Section: Npy In Diet-induced Obesity (Dio)mentioning

confidence: 99%

Neuropeptide Y in normal eating and in genetic and dietary-induced obesity

Beck

2006

Phil. Trans. R. Soc. B

218

129

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Neuropeptide Y (NPY) is one the most potent orexigenic peptides found in the brain. It stimulates food intake with a preferential effect on carbohydrate intake. It decreases latency to eat, increases motivation to eat and delays satiety by augmenting meal size. The effects on feeding are mediated through at least two receptors, the Y1 and Y5 receptors. The NPY system for feeding regulation is mostly located in the hypothalamus. It is formed of the arcuate nucleus (ARC), where the peptide is synthesized, and the paraventricular (PVN), dorsomedial (DMN) and ventromedial (VMN) nuclei and perifornical area where it is active. This activity is modulated by the hindbrain and limbic structures. It is dependent on energy availability, e.g. upregulation with food deprivation or restriction, and return to baseline with refeeding. It is also sensitive to diet composition with variable effects of carbohydrates and fats. Leptin signalling and glucose sensing which are directly linked to diet type are the most important factors involved in its regulation. Absence of leptin signalling in obesity models due to gene mutation either at the receptor level, as in the Zucker rat, the Koletsky rat or the db/db mouse, or at the peptide level, as in ob/ob mouse, is associated with increased mRNA abundance, peptide content and/or release in the ARC or PVN. Other genetic obesity models, such as the Otsuka-Long-Evans-Tokushima Fatty rat, the agouti mouse or the tubby mouse, are characterized by a diminution in NPY expression in the ARC nucleus and by a significant increase in the DMN. Further studies are necessary to determine the exact role of NPY in these latter models. Long-term exposure to high-fat or high-energy palatable diets leads to the development of adiposity and is associated with a decrease in hypothalamic NPY content or expression, consistent with the existence of a counter-regulatory mechanism to diminish energy intake and limit obesity development. On the other hand, an overactive NPY system (increased mRNA expression in the ARC associated with an upregulation of the receptors) is characteristic of rats or rodent strains sensitive to dietary-induced obesity. Finally, NPY appears to play an important role in body weight and feeding regulation, and while it does not constitute the only target for drug treatment of obesity, it may nevertheless provide a useful target in conjunction with others.

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“…Intriguingly, it has recently been reported that the anorexinergic effect of a new HTR2C agonist, BVT.X, is strictly associated with the activity of the melanocortin receptor 4 in the arcuate nucleus of the hypothalamus, and that HTR2C is coexpressed with neurons containing pro-opiomelanocortin [Lam et al, 2008]. Along with this, the role of HTR2C in the energy balance control has been widely demonstrated: a diet enriched in fat content was found to be associated with a downregulation of the HTR2C mRNA expression in rats [Schaffhauser et al, 2002], and the anorexinergic properties of lipopolysaccharide, IL-1 and leptin were shown to be under the control of HTR2C [von Meyenburg et al, 2003]. Moreover, HTR2C knock out animals show enhanced risk to develop obesity and impaired glucose homeostasis [Tecott et al, 1995;Wang and Chehab, 2006;Wade et al, 2008], and, intriguingly, it has been demonstrated that this is more evident after multiple stresses [Chou-Green et al, 2003].…”

mentioning

confidence: 94%

Focus on HTR2C: A possible suggestion for genetic studies of complex disorders

Drago

Serretti

2009

American J of Med Genetics Pt B

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HTR2C is one of the most relevant and investigated serotonin receptors. Its role in important brain structures such as the midbrain, the lateral septal complex, the hypothalamus, the olfactory bulb, the pons, the choroid plexus, the nucleus pallidus, the striatum and the amygdala, the nucleus accumbens and the anterior cingulated gyrus candidate it as a promising target for genetic association studies. The biological relevance of these brain structures is reviewed by way of the focus on HTR2C activity, with a special attention paid to psychiatric disorders. Evidence from the genetic association studies that dealt with HTR2C is reviewed and discussed alongside the findings derived from the neuronatmic investigations. The reasons for the discrepancies between these two sets of reports are discussed. As a result, HTR2C is shown to play a pivotal role in many different psychiatric behaviors or psychiatric related disrupted molecular balances, nevertheless, genetic association studies brought inconsistent results so far. The most replicated association involve the feeding behavior and antipsychotic induced side effects, both weight gain and motor related: Cys23Ser (rs6318) and -759C/T (rs3813929) report the most consistent results. The lack of association found in other independent studies dampens the clinical impact of these reports. Here, we report a possible explanation for discrepant findings that is poorly or not at all usually considered, that is that HTR2C may exert different or even opposite activities in the brain depending on the structure analyzed and that mRNA editing activity may compensate possible genetically controlled functional effects. The incomplete coverage of the HTR2C variants is proposed as the best cost-benefit ratio bias to fix. The evidence of brain area specific HTR2C mRNA editing opens a debate about how the brain can differently modulate stress events, and process antidepressant treatments, in different brain areas. The mRNA editing activity on HTR2C may play a major role for the negative association results.

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Effects of a High‐Fat Diet and Strain on Hypothalamic Gene Expression in Rats

Cited by 45 publications

References 60 publications

Complex HTR2C linkage disequilibrium and promoter associations with body mass index and serum leptin

Complex HTR2C linkage disequilibrium and promoter associations with body mass index and serum leptin

Neuropeptide Y in normal eating and in genetic and dietary-induced obesity

Focus on HTR2C: A possible suggestion for genetic studies of complex disorders

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