Para los judíos

A study has also shown that feeding mice an HFD for two months, where 58% of energy was provided by SFAs, suppressed hypothalamic neurogenesis (see Figure 1.21; McNay et al., 2012). This change was seen in the ARC and was linked to early apoptosis of newly proliferating cells. This decrease was partially reversed by calorie

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restriction. The same research group determined that centrally infused CNTF stimulated proliferation within the hypothalamus of these obese mice and caused sustained weight loss. Many of the newly proliferating cells demonstrated functional phenotypes relevant to energy balance, such as leptin sensitivity, but the mechanisms that allow HFD to inhibit neurogenesis remained unclear (see Figure 1.22; Kokoeva et al., 2005). However, the roles of circulating insulin and glucose have been linked with neurogenesis, as rodent models of diabetes show impaired hippocampal neurogenesis (Stranahan et al., 2008; Guo et al., 2010).

Figure 1.21. DIO inhibits adult hypothalamic neurogenesis. Sixteen-week-old mice were i.c.v. infused with BrdU for 7 days and brain tissue harvested 4 weeks later (A–C). The number of newborn (BrdU-labelled) cells was significantly reduced in the hypothalamus of DIO mice compared with that in lean controls. Scale bar: 100 µm. Data are mean ± SEM. n = 5 chow; n = 6 DIO. Abbreviations: BrdU= bromodeoxyuridine; DIO= diet-induced obesity. Source: McNay et al., 2012. J Clin Invest 122(1): 142-52.

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Figure 1.22. CNTF reduces body weight long term and induces cell proliferation in the hypothalamus. A: Mice were i.c.v infused for 7 days with BrdU (12 mg/day) in artificial cerebrospinal fluid alone or together with CNTF (0.75 mg/day). Body weight (BW) is shown as percentage difference from initial body weight (all data are mean ± SEM; n=5/group). B: BrdU-labelled cells in coronal sections of the hypothalamus at the level of the arcuate nucleus. Abbreviations: 3V= third ventricle; Arc= arcuate nucleus; BW= body weight; CNTF= ciliary neurotrophic factor; icv= intracerebroventricular; Me= median eminence. Source: Kokoeva et al., 2005. Science 310(5748): 679-83.

In contrast to these studies, Lee et al. (2012) demonstrated that young adult mice fed an HFD, providing a similar amount of energy from SFAs (60%), display active neurogenesis in the median eminence (see Figure 1.23a). Mice were fed up to 2.5 months of age (between postnatal days 5 and 75), after the diet had previously been supplied to their mothers. When this proliferation of cells was prevented, using irradiation (Figure 1.23c), weight gain was attenuated (Figure 1.23b) and energy expenditure and activity was increased (Figure 1.23d & e), suggesting a direct role for neurogenesis in body weight regulation. Interestingly, the rate of neurogenesis had increased significantly by postnatal day 75, indicating that HFD activation persists into adulthood, and suggests that it may modulate hypothalamic neural circuitry in later life.

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Figure 1.23. Young adult mice fed an HFD display active neurogenesis in the median eminence. P19 mice received BrdU (P10–P18), and hypothalamic sections were examined for BrdU immunostaining. (a) Hypothalamic proliferative zone (HPZ): enriched BrdU+ cell population (green) along the median eminence (MEm) ependymal layer of 3V floor. Sections counterstained with DAPI (blue), a nuclear marker. Scale bar: 50 µm. (b) Attenuated weight gain in HFD-fed irradiated mice compared with sham controls (n = 9). (c) MEm neurogenesis reduced in irradiated versus sham-irradiated mice (n = 4). (d) Higher energy expenditure observed in irradiated mice (n = 11). (e) Higher total activity observed in irradiated mice (n = 11). Mean ±SEM; *P < 0.05, **P < 0.01; ***P < 0.01. Abbreviations: 3V= third ventricle; ArcN= arcuate nucleus; BrdU= bromodeoxyuridine; HFD= high-fat diet; HPZ= hypothalamic proliferative zone; MEm= median eminence; Rad= irradiated Source: adapted from Lee et al., 2012. Nat Neurosci 15(5): 700-2.

This idea is further supported by the work of Chang et al. (2008) who had observed that offspring of rat dams fed a high-fat diet (50% of energy from SFAs) displayed increased proliferation of neural stem cells (NSCs) and neural progenitor

cells (NPCs) in the hypothalamus which prevailed at least until termination at

postnatal day 70. In addition, enhanced differentiation and migration toward hypothalamic regions where these neurons ultimately expressed orexigenic peptides was also seen. This was linked with an increase in circulating lipids (triglycerides and free fatty acids) in the dams and offspring. Although a precise mechanism had not been determined, it was proposed that the purpose of this neurogenesis was to

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prepare the juveniles for the increased food intake and high-fat diet preference they would probably show after weaning (Chang et al., 2008).

In contrast, another study demonstrated that the number of adult hypothalamic NSCs in the VMH of three-month old mice was reduced and the process impaired following the chronic consumption of an HFD (58% energy from SFAs). Following an additional month of feeding this inhibition was even more severe. This was linked to the proinflammatory pathway involving IқB kinase β

(IKKβ) and the downstream nuclear factor –қB (NF-қB) which mediates HFD-

induced hypothalamic inflammation. Activation of the IKKβ and NF-қB pathways

impairs the regulation of cell survival, growth, apoptosis and differentiation contributing to the neurodegenerative mechanism of obesity and related diabetes (Li et al., 2012). This study differs from that of Lee et al. (2012), as short-term HFD feeding was reported to promote hypothalamic neurogenesis in juveniles, whereas long-term (4-month) HFD feeding described by Li et al. (2012) remarkably depleted

hypothalamic NSCs and impaired neuronal differentiation. Li et al. suggest that

whereas neurogenic upregulation by short-term HFD feeding may represent a compensatory reaction, long-term HFD feeding is detrimental for the cell fate of adult hypothalamic NSCs. They suggest that the neurodegenerative actions of chronic HFD feeding are attributed to IKKβ and NF-қB pathway overactivation, concluding that these NSCs are vulnerable to hypothalamic inflammation induced by chronic HFD feeding (Li et al., 2012).

In contrast, another study has found no effect of HFD feeding on cell proliferation or neurogenesis in the hypothalamus or the hippocampus of rats fed a diet containing 60% of energy from SFAs for three months (Rivera et al., 2011). Despite the rats developing obesity, there were no differences in neurogenesis, when compared to a low-fat-fed control group, in the SGZ, SVZ or hypothalamus, consistent with similar concentrations of metabolism markers (plasma adiponectin, insulin and leptin concentrations) between the groups. The lack of effects may have been due to dietary composition, as sucrose and lard were present in both the high- fat diet and low fat control diets. This may have led to some metabolic dysfunction in the control group such that metabolic markers failed to differ.

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