Body weight represents a balance between food intake and energy expenditure [1]. Energy expenditure can be obligatory, due to physical activity, or the result of adaptive thermogenesis. In mice, adaptive thermogenesis is largely promoted by uncoupling protein-1 (UCP1) in brown adipose tissue, although white adipose tissue may also participate through the regulated expression of this protein [2]. Our lab has recently shown that the IKK family member, IKKi (Ikbke), is an important mediator of systemic inflammation, insulin resistance, hepatic steatosis, body weight, and energy expenditure in the context of diet-induced obesity [3]. IKKi expression and activity are dramatically increased in mice on a high fat diet in both liver and white adipose tissue. High fat-fed Ikbke -/- mice do not gain weight like wild type mice due to increased thermogenesis, resulting from UCP1 mRNA and protein up regulation in white adipose tissue. Therefore, I will investigate the relationship between IKKi and energy balance in white adipocytes according to the following specific aims: 1. Does IKKi regulate energy expenditure in white adipocytes during high fat diet through increased thermogenesis? I hypothesize that elevations in energy expenditure observed in Ikbke -/- mice are due to increased thermogenesis arising from UCP1 expression in white adipocytes. I will examine thermogenic markers during a time- course of high fat diet in both wild type and Ikbke -/- mice. I will also evaluate these parameters in response to cold exposure or administration of 2-adrenergic agonists. I will measure respiration rates and uncoupled respiration in primary white adipocytes from wild type and Ikbke -/- mice. I will also begin efforts to create conditional Ikbke -/- mice, allowing me to specifically evaluate the role of the protein in adipose tissue. 2. What are the substrates of IKKi that mediate its transcriptional effects in white adipocytes? I hypothesize that upon its elevation, IKKi suppresses the adaptive increase in UCP1 expression in white adipocytes, thereby preventing increased energy expenditure, and producing weight gain. I will identify the substrates of IKKi in white adipocytes, and determine their importance for regulation of UCP1 expression. I will examine candidates based on known IKKi substrates;evaluate the -adrenergic signaling pathway, and focus on transcription factors known to regulate the UCP1 proximal promoter. I will also use a recently developed phospho-motif IKKi substrate antibody to identify other potential physiological substrates of IKKi.

Public Health Relevance

Obesity is a central feature of a vast array of diseases including type 2 diabetes, atherosclerosis, asthma, and cancer. We are pursuing how IKKi, a protein, leads to obesity and obesity-related disorders when animals are on a high fat diet. This research will contribute to our understanding of obesity and will point to therapeutic interventions of these conditions.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZDK1-GRB-W (M1))
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Castle, Arthur
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University of Michigan Ann Arbor
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Ann Arbor
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Reilly, Shannon M; Chiang, Shian-Huey; Decker, Stuart J et al. (2013) An inhibitor of the protein kinases TBK1 and IKK-É› improves obesity-related metabolic dysfunctions in mice. Nat Med 19:313-21
Mowers, Jonathan; Uhm, Maeran; Reilly, Shannon M et al. (2013) Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKKε and TBK1. Elife 2:e01119