Emerging evidence suggests that new cells, including neurons, can be generated within the adult hypothalamus, suggesting the existence of a local neural stem/progenitor cell niche. Here, we identify a-tanycytes as key components of a hypothalamic niche in the adult mouse. Long-term lineage tracing in vivo using a GLAST::CreER T2 conditional driver indicates that a-tanycytes are self-renewing cells that constitutively give rise to new tanycytes, astrocytes and sparse numbers of neurons. In vitro studies demonstrate that a-tanycytes, but not b-tanycytes or parenchymal cells, are neurospherogenic. Distinct subpopulations of a-tanycytes exist, amongst which only GFAP-positive dorsal a2-tanycytes possess stem-like neurospherogenic activity. Fgf-10 and Fgf-18 are expressed specifically within ventral tanycyte subpopulations; a-tanycytes require fibroblast growth factor signalling to maintain their proliferation ex vivo and elevated fibroblast growth factor levels lead to enhanced proliferation of a-tanycytes in vivo. Our results suggest that a-tanycytes form the critical component of a hypothalamic stem cell niche, and that local fibroblast growth factor signalling governs their proliferation.

In the CNS, the hypothalamic arcuate nucleus (ARN) energy-balance circuit plays a key role in regulating body weight. Recent studies have shown that neurogenesis occurs in the adult hypothalamus, revealing that the ARN energy-balance circuit is more plastic than originally believed. Changes in diet result in altered gene expression and neuronal activity in the ARN, some of which may reflect hypothalamic plasticity. To explore this possibility, we examined the turnover of hypothalamic neurons in mice with obesity secondary to either high-fat diet (HFD) consumption or leptin deficiency. We found substantial turnover of neurons in the ARN that resulted in ongoing cellular remodeling. Feeding mice HFD suppressed neurogenesis, as demonstrated by the observation that these mice both generated fewer new neurons and retained more old neurons. This suppression of neuronal turnover was associated with increased apoptosis of newborn neurons. Leptin-deficient mice also generated fewer new neurons, an observation that was explained in part by a loss of hypothalamic neural stem cells. These data demonstrate that there is substantial postnatal turnover of the arcuate neuronal circuitry in the mouse and reveal the unexpected capacity of diet and leptin deficiency to inhibit this neuronal remodeling. This insight has important implications for our understanding of nutritional regulation of energy balance and brain function. IntroductionThe hypothalamus is a critical regulator of energy balance. Lesions of the ventromedial nucleus (1) or arcuate nucleus (ARN) (2) result in obesity, while lesions of the lateral hypothalamic area (3) result in weight loss. Energy-related signals such as leptin (4, 5) are integrated by responsive neurons in the ARN and ventromedial hypothalamus. In particular, leptin stimulates the anorexigenic proopiomelanocortin (POMC) neurons and inhibits orexigenic neuropeptide Y (NPY) neurons. In situations of negative energy balance, reduced leptin levels inhibit the activity of POMC neurons and activate NPY neurons. While this feedback circuit is essential for normal energy homeostasis (see review refs. 6, 7), most obesity is associated with dysregulation of the circuit and leptin resistance (8).Two commonly studied mouse models of obesity, the high-fat diet-induced (HFD-induced) obesity (DIO) model (9) and the more severe obesity arising from the lack of leptin (4, 5), share features such as increased fat mass, hyperglycemia, hyperinsulinemia, and activation of the adrenal axis but are distinct in that DIO mice have elevated peripheral leptin levels and are resistant to both endogenous and exogenous leptin (8). DIO mice also become resistant to centrally administered leptin (10). This phenomenon is reversible, with leptin responsiveness returning several months after cessation of HFD consumption (11).The molecular and cellular mechanisms underlying hypothalamic dysfunction in the context of obesity over long-time frames are still not fully understood. Possible mechanisms include impaired leptin transport acr...

HNF4α has been implicated in colitis and colon cancer in humans but the role of the different HNF4α isoforms expressed from the two different promoters (P1 and P2) active in the colon is not clear. Here, we show that P1-HNF4α is expressed primarily in the differentiated compartment of the mouse colonic crypt and P2-HNF4α in the proliferative compartment. Exon swap mice that express only P1- or only P2-HNF4α have different colonic gene expression profiles, interacting proteins, cellular migration, ion transport and epithelial barrier function. The mice also exhibit altered susceptibilities to experimental colitis (DSS) and colitis-associated colon cancer (AOM+DSS). When P2-HNF4α-only mice (which have elevated levels of the cytokine resistin-like β, RELMβ, and are extremely sensitive to DSS) are crossed with Retnlb-/- mice, they are rescued from mortality. Furthermore, P2-HNF4α binds and preferentially activates the RELMβ promoter. In summary, HNF4α isoforms perform non-redundant functions in the colon under conditions of stress, underscoring the importance of tracking them both in colitis and colon cancer.DOI: http://dx.doi.org/10.7554/eLife.10903.001