Abstract
The mechanisms that link diet and body weight are not fully understood. A diet high in fat often leads to obesity, and this in part is the consequence of diet-induced injury to specific hypothalamic nuclei. It has been suggested that a diet high in fat leads to cell loss in the lateral hypothalamus, which contains specific populations of neurons that are essential for regulating energy homoeostasis; however, we do not know which cell types are affected by the diet. We studied the possibility that high-fat diet leads to a reduction in orexin-A/hypocretin-1 (Hcrt1) and/or melanin-concentrating hormone (MCH) immunoreactivity in the lateral hypothalamus. We quantified immuno-labeled Hcrt1 and MCH cells in brain sections of mice fed a diet high in fat for up to 12 weeks starting at 4 weeks of age and found that this diet did not modify the number of Hcrt1- or MCH-immunoreactive neurons. By contrast, there were fewer Hcrt1- (but not MCH-) immunoreactive cells in genetically obese db/db mice compared to wild-type mice. Non-obese, heterozygous db/+ mice also had fewer Hcrt1-immunoreactive cells. Differences in the number of Hcrt1-immunoreactive cells were only a function of the db genotype but not of diet or body weight. Our findings show that the lateral hypothalamus is affected differently in the db genotype and in diet-induced obesity, and support the idea that not all hypothalamic neurons involved in energy balance regulation are sensitive to the effects of diet.
Highlights
A diet high in fat often leads to obesity and type 2 diabetes in both humans and animals (Astrup et al, 2008) but the mechanisms that link diet and metabolic disease are not fully understood
We do not know if melanin-concentrating hormone (MCH) and O/H cells of the lateral hypothalamus are affected by a high-fat diet intake
Db/db mice were much heavier than control db/+ mice (strain, F(1, 13) = 173.82, p = 6.7 × 10−9; age, F(1, 13) = 21.73, p = 0.0004; two factor ANOVA), and there was no significant interaction between animal strain and age (8 or 14 weeks old) (F(1, 12) = 0.149, p = 0.706) which suggests that the marked difference in body weight was already established by the time the animals were 8 weeks of age (Fig. 2B)
Summary
A diet high in fat often leads to obesity and type 2 diabetes in both humans and animals (Astrup et al, 2008) but the mechanisms that link diet and metabolic disease are not fully understood. One consequence of high-fat diet intake is damage to the hypothalamus, which is an essential component of the network that regulates appetite and metabolism in the body (Waterson & Horvath, 2015). Much of the damage that is seen in the arcuate following high-fat diet seems to preferentially affect neurones involved in appetite regulation, namely orexigenic neurones that express neuropeptide Y and anorexigenic neurones that express the peptide pro-opiomelanocortin (Moraes et al, 2009; Horvath et al, 2010). We do not know if MCH and O/H cells of the lateral hypothalamus are affected by a high-fat diet intake
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