Conditional deletion of melanin-concentrating hormone receptor 1 from GABAergic neurons increases locomotor activity.

Objective: Melanin-concentrating hormone (MCH) plays a key role in regulating energy balance. MCH acts via its receptor MCHR1, and MCHR1 deletion increases energy expenditure and locomotor activity, which is associated with a hyperdopaminergic state. Since MCHR1 expression is widespread, the neurons supporting the effects of MCH on energy expenditure are not clearly defined.

Opposing roles of nuclear receptor HNF4α isoforms in colitis and colitis-associated colon cancer.

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.

Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice.

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.

Combined neural inactivation of suppressor of cytokine signaling-3 and protein-tyrosine phosphatase-1B reveals additive, synergistic, and factor-specific roles in the regulation of body energy balance.

Objective: The adipokine hormone leptin triggers signals in the brain that ultimately lead to decreased feeding and increased energy expenditure. However, obesity is most often associated with elevated plasma leptin levels and leptin resistance. Suppressor of cytokine signaling (SOCS)-3 and protein-tyrosine phosphatase 1B (PTP-1B) are two endogenous inhibitors of tyrosine kinase signaling pathways and suppress both insulin and leptin signaling via different molecular mechanisms.

Characterization of glucocorticoid receptor and hepatocyte nuclear factor 4alpha (HNF4alpha) binding to the hnf4alpha gene in the liver.

Hepatocyte nuclear factor 4alpha (HNF4alpha) plays a crucial role in hepatocyte differentiation, liver organogenesis and regulation of liver functions. In mouse liver, HNF4alpha is expressed from two promoters, P1 and P2, the latter being very weakly active and only in the embryo. Previously, using transfection assays we identified an enhancer upstream of P1 that mediates both HNF4alpha transactivation and glucocorticoid induction and showed that HNF4alpha1, originated from P1, represses activity of the P2 promoter, possibly through its indirect recruitment to the promoter.

In vivo role of the HNF4alpha AF-1 activation domain revealed by exon swapping.

The gene encoding the nuclear receptor hepatocyte nuclear factor 4alpha (HNF4alpha) generates isoforms HNF4alpha1 and HNF4alpha7 from usage of alternative promoters. In particular, HNF4alpha7 is expressed in the pancreas whereas HNF4alpha1 is found in liver, and mutations affecting HNF4alpha function cause impaired insulin secretion and/or hepatic defects in humans and in tissue-specific 'knockout' mice. HNF4alpha1 and alpha7 isoforms differ exclusively by amino acids encoded by the first exon which, in HNF4alpha1 but not in HNF4alpha7, includes the activating function (AF)-1 transactivation domain.

Expression of the alpha7 isoform of hepatocyte nuclear factor (HNF) 4 is activated by HNF6/OC-2 and HNF1 and repressed by HNF4alpha1 in the liver.

The hepatocyte nuclear factor (HNF) 4alpha gene possesses two promoters, proximal P1 and distal P2, whose use results in HNF4alpha1 and HNF4alpha7 transcripts, respectively. Both isoforms are expressed in the embryonic liver, whereas HNF4alpha1 is almost exclusively in the adult liver. A 516-bp fragment, encompassing a DNase I-hypersensitive site associated with P2 activity that is still retained in adult liver, contains functional HNF1 and HNF6 binding sites and confers full promoter activity in transient transfections.