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1.  Disruption of hypothalamic leptin signaling in mice leads to early-onset obesity, but physiological adaptations in mature animals stabilize adiposity levels 
The Journal of Clinical Investigation  2010;120(8):2931-2941.
Distinct populations of leptin-sensing neurons in the hypothalamus, midbrain, and brainstem contribute to the regulation of energy homeostasis. To assess the requirement for leptin signaling in the hypothalamus, we crossed mice with a floxed leptin receptor allele (Leprfl) to mice transgenic for Nkx2.1-Cre, which drives Cre expression in the hypothalamus and not in more caudal brain regions, generating LeprNkx2.1KO mice. From weaning, LeprNkx2.1KO mice exhibited phenotypes similar to those observed in mice with global loss of leptin signaling (Leprdb/db mice), including increased weight gain and adiposity, hyperphagia, cold intolerance, and insulin resistance. However, after 8 weeks of age, LeprNkx2.1KO mice maintained stable adiposity levels, whereas the body fat percentage of Leprdb/db animals continued to escalate. The divergence in the adiposity phenotypes of Leprdb/db and LeprNkx2.1KO mice with age was concomitant with increased rates of linear growth and energy expenditure in LeprNkx2.1KO mice. These data suggest that remaining leptin signals in LeprNkx2.1KO mice mediate physiological adaptations that prevent the escalation of the adiposity phenotype in adult mice. The persistence of severe adiposity in LeprNkx2.1KO mice, however, suggests that compensatory actions of circuits regulating growth and energy expenditure are not sufficient to reverse obesity established at an early age.
doi:10.1172/JCI41985
PMCID: PMC2912188  PMID: 20592471
2.  Respective Contributions of Maternal Insulin Resistance and Diet to Metabolic and Hypothalamic Phenotypes of Progeny 
Obesity (Silver Spring, Md.)  2010;19(3):492-499.
Maternal obesity can influence susceptibility to obesity and type 2 diabetes in progeny. We examined the relationship of maternal insulin resistance (IR), a metabolically important consequence of increased adiposity, to adverse consequences of obesity for fetal development. We used mice heterozygous for a null allele of the insulin receptor (Insr) to study the contributions of maternal IR to offspring phenotype without the potential confound of obesity per se, and how maternal consumption of high-fat diet (HFD) may, independently and interactively, affect progeny. In progeny fed a 60% HFD, body weight and adiposity were transiently (5–7 weeks) increased in wild-type (+/+) offspring of Insr+/− HFD-fed dams compared to offspring of wild-type HFD-fed dams. Offspring of HFD-fed wild-type dams had increased body weight, blood glucose, and plasma insulin concentrations compared to offspring of chow-fed wild-type dams. Quantification of proopiomelanocortin (POMC) and neuropeptide-Y (NPY) populations in the arcuate nucleus of the hypothalamus (ARH) of offspring of wild-type vs. Insr+/− dams was performed to determine whether maternal IR affects the formation of central feeding circuits. We found a 20% increase in the number of Pomc-expressing cells at postnatal day 9 in offspring of Insr+/− dams. In conclusion, maternal HFD consumption—distinct from overt obesity per se—was a major contributor to increased body weight, adiposity, IR, and liver triglyceride (TG) phenotypes in progeny. Maternal IR played a minor role in predisposing progeny to obesity and IR, though it acted synergistically with maternal HFD to exacerbate early obesity in progeny.
doi:10.1038/oby.2010.245
PMCID: PMC3234171  PMID: 20948526
3.  Differential Gene Expression Between Neuropeptide Y Expressing Neurons of the Dorsomedial Nucleus of the Hypothalamus and the Arcuate Nucleus: Microarray Analysis Study 
Brain research  2010;1350:139-150.
The Dorsomedial Nucleus of the Hypothalamus (DMH) is known to play important roles in ingestive behavior and body weight homeostasis. The DMH contains neurons expressing Neuropeptide Y (NPY) during specific physiological conditions of hyperphagia and obesity, however, the role of DMH-NPY neurons has yet to be characterized. In contrast to the DMH-NPY neurons, NPY expressing neurons have been best characterized in the Arcuate Nucleus of the Hypothalamus (ARH). The purpose of this study is to characterize the chemical phenotype of DMH-NPY neurons by comparing the gene expression profiles of NPY neurons in the DMH and ARH isolated from postnatal NPY-hrGFP mice by microarray analysis.
Twenty genes were differentially expressed in the DMH-NPY neurons compared to the ARH. Among them, there were several transcriptional factors that play important roles in the regulation of energy balance. DMH-NPY neurons expressed Glutamic Acid Decarboxylase (GAD) 65 and 67, suggesting that they may be GABAergic, similar to ARH-NPY neurons. While ARH-NPY neurons expressed leptin receptor (ObRb) and displayed the activation of STAT3 in response to leptin administration, DMH-NPY neurons showed neither. These findings strongly suggest that DMH-NPY neurons could play a distinct role in the control of energy homeostasis and are differentially regulated from ARH-NPY neurons through afferent inputs and transcriptional regulators.
doi:10.1016/j.brainres.2010.03.082
PMCID: PMC2917610  PMID: 20380814
5.  Regulation of Fto/Ftm gene expression in mice and humans 
Two recent, large GWAS in European populations have associated a ∼47 Kb region that contains part of the FTO gene with high BMI. The functions of FTO and adjacent FTM in human biology are not clear. We examined expression of these genes in organs of mice segregating for monogenic obesity mutations, exposed to under/over feeding, and to 4 °C. Fto/Ftm expression was reduced in mesenteric adipose tissue of mice segregating for the Ay, Lepob, Leprdb, Cpefat or tub mutations and there was a similar trend in other tissues. These effects were not due to adiposity per se. Hypothalamic Fto and Ftm expression were decreased by fasting in lean and obese animals and by cold exposure in lean mice. The fact that responses of Fto and Ftm expression to these manipulations were almost indistinguishable suggested that the genes might be co-regulated. The putative overlapping regulatory region contains at least 2 canonical CUTL1 binding sites. One of these nominal CUTL1 sites includes rs8050136, a SNP associated with high body mass. The A allele of rs8050136 – associated with lower body mass than the C allele – preferentially bound CUTL1 in human fibroblast DNA. 70% knockdown of CUTL1 expression in human fibroblasts decreased FTO and FTM expression by 90 and 65 %, respectively. Animals and humans with various genetic interruptions of FTO or FTM have phenotypes reminiscent of aspects of the Bardet-Biedl obesity syndrome, a confirmed “ciliopathy”. FTM has recently been shown to be a ciliary basal body protein.
doi:10.1152/ajpregu.00839.2007
PMCID: PMC2808712  PMID: 18256137
obesity; hypothalamus; adipose tissue; CUTL1

Results 1-5 (5)