De NovoNeurogenesis in Adult Hypothalamus as a Compensatory Mechanism to Regulate Energy Balance

Abstract

The ability to develop counter-regulatory mechanisms to maintain energy balance in response to environmental and physiologic insults is essential for survival, but the mechanisms underlying these compensatory regulations are poorly understood. Agouti-related peptide (AGRP) and Neuropeptide Y are potent orexigens and are coexpressed in neurons in the arcuate nucleus of the hypothalamus. Acute ablation of these neurons leads to severe anorexia and weight loss, whereas progressive degeneration of these neurons has minimal impact on food intake and body weight, suggesting that compensatory mechanisms are developed to maintain orexigenic drive. In this study, we show that cell proliferation is increased in the hypothalamus of adult mutant animals in which AgRP neurons undergo progressive neurodegeneration due to deletion of mitochondrial transcription factor A, and that a subset of these newly generated cells differentiate into AgRP neurons along with other resident neuronal subtypes. Furthermore, some of the newly generated cells are capable of responding to leptin, and a central blockade of cell proliferation in adult animals results in decreases in food intake and body adiposity in mutant but not in control animals. Our study indicates that neurons important for energy homeostasis can be regenerated in adult feeding centers under neurodegenerative conditions. It further suggests that de novo neurogenesis might serve as a compensatory mechanism contributing to the plastic control of energy balance in response to environmental and physiologic insults.

Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors

“…The majority of BrdU-labeled cells are colabeled with the mature neuronal marker NeuN, and this percentage does not differ between groups when assessed throughout the whole, dorsal, or ventral hippocampus (P40.05). whether hypothalamic adult neurogenesis is affected in iBax mice, we performed analysis of the number of BrdU-labeled cells in the arcuate nucleus, a portion of the hypothalamus where the presence of adult-born cells has been reported (Kokoeva et al, 2005;Pierce and Xu, 2010;Xu et al, 2005). We observed no difference in the numbers of BrdU-labeled cells between vehicle-and TAM-treated mice (F(1,8) = 1.694, P40.05) (Figure 1d).…”

Noncanonical Sites of Adult Neurogenesis in the Mammalian Brain

“…In adult rodents, most parenchymal neurogenesis seems to occur spontaneously at very low levels, rather being elicited/enhanced after specific physiological or pathological conditions (see below) (Dayer et al 2005;Kokoeva et al 2005;Luzzati et al 2006;Ponti et al 2008;Ohira et al 2010;Pierce and Xu 2010). Dayer and colleagues (2005) showed the occurrence of new neurons in the deep layers of the rat cerebral cortex.…”

“…There are several convincing studies showing constitutive neurogenesis in the adult hypothalamus of mammals, including rodents, rats, mice, voles (Pencea et al 2001;Kokoeva et al 2005;Xu et al 2005;Matsuzaki et al 2009;Perez-Martin et al 2010;Pierce and Xu 2010;Li et al 2012;Werner et al 2012), and sheep (Migaud et al 2011) using BrdU as well as genetic lineage tracing. BrdU was injected intraperitoneally (repeated injections except in Migaud et al 2011) or infused intracerebroventricularly (Kokoeva et al 2005;Li et al 2012); 6 to 53 d postinjection immunostaining for neuronal markers (e.g., DCX and NeuN) as well as glial markers (e.g., glial fibrillary acidic protein [GFAP] for astrocytes) were performed.…”

“…Newborn neurons acquire identities and functional phenotypes relevant for energy-balance regulation. A subset of newborn neurons express the anorexigenic marker proopiomelanocortin (POMC) and the orexigenic markers, neuropeptide-Y ( Kokoeva et al 2005;Li et al 2012;Haan et al 2013) and agouti-related protein (AgRP) (Pierce and Xu 2010), and respond to fasting and leptininduced signaling (Kokoeva et al 2005;Pierce and Xu 2010;Haan et al 2013). Leptin, produced by white adipose tissue, plays a funda- mental role in maintaining neuroendocrine and body weight homeostasis.…”

α-Tanycytes of the adult hypothalamic third ventricle include distinct populations of FGF-responsive neural progenitors

“…In addition, in vivo analyses show constitutive proliferation, neurogenesis and astrocyte generation within a third region of the adult brain, the hypothalamus [1][2][3][4][5] . Here, neurogenesis and gliogenesis can be attenuated through the manipulation of secreted trophic factors, de novo neurogenesis, in particular, associated with energy balance 1,2,4,6,7 .…”