Over the past half century, obesity has become a widespread concern to human health. Obesity is defined as having a body mass index above 30 and is accompanied by altered metabolic physiology. Obesity is one of the leading causes of mortality in the United States and in the world. The prevalence of obesity has increased over the past few decades. High body fat in adipose, excess calorie intake, low aerobic fitness are all associated with the comorbidities of obesity. Recently, an emphasis has been given to increased leukocytes in adipose tissue and the resulting low-grade systemic inflammation on the development of insulin resistance. Unfortunately, the immune-metabolic molecular mechanisms by which increased inflammation leads to diseases is not fully understood.
We studied Nucb2, a highly expressed gene in immune cells and encodes for nesfatin-1, a peptide reported to be a satiety signal. We saw that Nucb2 expression is increased in leukocytes of high fat diet (HFD) fed animals. Contrary to our hypothesis, Nucb2-/- animals showed no effect on food intake. We then performed euglycemic hyperinsulinemic clamp studies in wild type and Nucb2 mice on a chow diet and a HFD to determine insulin sensitivity. Interestingly, knocking out the Nucb2 gene significantly impaired insulin sensitivity only under HFD conditions. These experiments demonstrate that Nucb2 is key player in glucose homeostasis in obesity.
We discovered macrophages deficient of Nucb2 impact the proinflammatory macrophages. Macrophages lacking Nucb2 increased proinflammatory cytokine production. This suggests that Nucb2 intrinsically regulates the inflammatory cytokine production cascade.
Mechanistically, Nucb2 mediates its effects by increasing proinflammatory cytokine expression via down-regulation of NFκB signaling in leukocytes. In the absence of Nucb2, NFκB activity is increased in macrophages. In contrast, inhibiting NFκB caused the opposite response. Finally, in response to endotoxemia, Nucb2 is required to control the production proinflammatory cytokines. Collectively, these data highlight a novel mechanism whereby Nucb2 serves as a key mediator of immunometabolic control of inflammation and insulin resistance. Overall, the studies I have performed identified a novel mediator of the immune-metabolic cross talks in the context of obesity-induced insulin resistance.
| Identifer | oai:union.ndltd.org:LSU/oai:etd.lsu.edu:etd-06022016-150032 |
| Date | 13 June 2016 |
| Creators | Ravussin, Anthony |
| Contributors | Batzer, Mark A., Dixit, Vishwa D., Stephens, Jacqueline, DiMario, Patrick J., Singh, Parampreet |
| Publisher | LSU |
| Source Sets | Louisiana State University |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lsu.edu/docs/available/etd-06022016-150032/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached herein a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to LSU or its agents the non-exclusive license to archive and make accessible, under the conditions specified below and in appropriate University policies, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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