SUMMARYWnt1-expressing progenitors generate midbrain dopamine (MbDA) and cerebellum (Cb) neurons in distinct temporal windows and from spatially discrete progenitor domains. It has been shown that Wnt1 and Lmx1a participate in a cross-regulatory loop that is utilized during MbDA neuron development. However, Wnt1 expression dynamically changes over time and precedes that of Lmx1a. The spatial and temporal requirements of Wnt1 in development and specifically its requirement for MbDA neurons remain to be determined. To address these issues, we generated a conditional Wnt1 allele and temporally deleted Wnt1 coupled with genetic lineage analysis. Using this approach, we show that patterning of the midbrain (Mb) and Cb by Wnt1 occurs between the one-somite and the six-to eight-somite stages and is solely dependent on Wnt1 function in the Mb, but not in the Cb. Interestingly, an En1-derived domain persists after the early deletion of Wnt1 and mutant cells express OTX2. However, the En1-derived Wnt1-mutant domain does not contain LMX1a-expressing progenitors, and MbDA neurons are depleted. Thus, we demonstrate an early requirement of Wnt1 for all MbDA neurons. Subsequently, we deleted Wnt1 in the ventral Mb and show a continued late requirement for Wnt1 in MbDA neuron development, but not in LMX1a-expressing progenitors. Specifically, Wnt1 deletion disrupts the birthdating of MbDA neurons and causes a depletion of MbDA neurons positioned medially and a concomitant expansion of MbDA neurons positioned laterally during embryogenesis. Collectively, our analyses resolve the spatial and temporal function of Wnt1 in Mb and Cb patterning and in MbDA neuron development in vivo.

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The IκB kinase β (IKKβ) is a master kinase involved in obesity-related inflammation and insulin resistance through nuclear factor κB dependent and independent pathways. However, the effect of IKKβ activation in adipose tissue, the organ critical for storage of excessive energy and initiation of inflammatory responses in the context of obesity, on systemic insulin sensitivity and metabolism, has not been investigated. In our study, we found that mice overexpressing the constitutively active IKKβ in adipose tissue under the control of murine adipocyte fatty acid binding protein (aP2) promoter were protected from age-related and diet-induced body weight gains, despite increased food intake. The aP2-IKKβ SE mice have significantly reduced weights in all white adipose tissue depots and reduced triglyceride contents in adipose tissue, liver, and muscle. Despite increased systemic and tissue inflammation, aP2-IKKβ SE mice displayed decreased blood glucose levels, improved glucose, and insulin tolerance. This may be at least partially attributable to increased energy expenditure. Histological analysis revealed presence of many small adipocytes in white adipose tissue of aP2-IKKβ SE mice fed on high-fat diet. Furthermore, transgenic expression of IKKβ in adipose tissue improved high-fat diet-induced hepatosteatosis. Collectively, increased energy expenditure and reduced plasma free fatty acid levels may contribute to enhanced systemic insulin sensitivity in aP2-IKKβ SE mice. Our study demonstrates that presence of inflammation in adipose tissue before the development of obesity has beneficial effect on metabolism.