ABSTRACT
BACKGROUND: Obesity induces significant changes in lipid mediators, however, the extent to which these changes persist after weight loss has not been investigated. SUBJECTS/METHODS: We fed C57BL6 mice a high-fat diet to generate obesity and then switched the diet to a lower-fat diet to induce weight loss. We performed a comprehensive metabolic profiling of lipid mediators including oxylipins, endocannabinoids, sphingosines and ceramides in key metabolic tissues (including adipose, liver, muscle and hypothalamus) and plasma. RESULTS: We found that changes induced by obesity were largely reversible in most metabolic tissues but the adipose tissue retained a persistent obese metabolic signature. Prostaglandin signaling was perturbed in the obese state and lasting increases in PGD2, and downstream metabolites 15-deoxy PGJ2 and delta-12-PGJ2 were observed after weight loss. Furthermore expression of the enzyme responsible for PGD2 synthesis (hematopoietic prostaglandin D synthase, HPGDS) was increased in obese adipose tissues and remained high after weight loss. We found that inhibition of HPGDS over the course of 5 days resulted in decreased food intake in mice. Increased HPGDS expression was also observed in human adipose tissues obtained from obese compared with lean individuals. We then measured circulating levels of PGD2 in obese patients before and after weight loss and found that while elevated relative to lean subjects, levels of this metabolite did not decrease after significant weight loss. CONCLUSIONS: These results suggest that lasting changes in lipid mediators induced by obesity, still present after weight loss, may play a role in the biological drive to regain weight.
Subject(s)
Lipid Metabolism/physiology , Metabolome/physiology , Obesity/metabolism , Weight Loss/physiology , Adipocytes , Animals , Body Weight/physiology , Cells, Cultured , Diet, Fat-Restricted , Diet, High-Fat , Eating/physiology , Humans , Male , Mice , Mice, Inbred C57BL , Organ Specificity/physiologyABSTRACT
The proinflammatory cytokine Interleukin 1 beta (IL-1beta) is elevated in obese individuals and rodents and it is implicated in impaired insulin secretion, decreased cell proliferation and apoptosis of pancreatic beta cells. In this study we describe the therapeutic effects by an IL-1beta antibody to improve glucose control in hyperglycemic mice with diet-induced obesity. After 13 weeks of treatment the IL-1beta antibody treated group showed reduced glycated hemoglobin (( *)P=0.049), reduced serum levels of proinsulin (( *)P=0.015), reduced levels of insulin and smaller islet size (( *)P=1.65E-13) relative to the control antibody treated group. Neutralization of IL-1beta also significantly reduced serum amyloid A (SAA) which is an indicator of inflammation-induced acute phase response (( *)P=0.024). While there was no improvement of obesity, a significant improvement of glycemic control and of beta cell function is achieved by this pharmacological treatment which may slow/prevent disease progression in Type 2 Diabetes.
Subject(s)
Blood Glucose/metabolism , Interleukin-1beta/immunology , Obesity/physiopathology , Animals , Antibodies/therapeutic use , Diet , Glycated Hemoglobin/metabolism , Insulin Resistance/physiology , Male , Mice , Obesity/drug therapy , Serum Amyloid A Protein/metabolismABSTRACT
Genetic loci for autosomal dominant pure hereditary spastic paraplegia (ADPHSP) have been mapped to chromosomes 2p, 8q, 12q, 14q, and 15q. We undertook a genomewide linkage screen of a large family with ADPHSP, for which linkage at all previously identified ADPHSP loci was excluded. Analysis of markers on chromosome 19q gave a peak pairwise LOD score of 3.72 at D19S420, allowing assignment of a novel ADPHSP locus (which we have termed "SPG12") to this region. Haplotype construction and analysis of recombination events narrowed the SPG12 locus to a 16.1-cM region between markers D19S868 and D19S902.
