The recent rediscovery of human brown adipose tissue through PET-CT has initiated more research on thermogenesis and defense defense against obesity. Many studies have demonstrated that white adipose tissue (WAT) in mice has the ability to upregulate its thermogenic capacity and become beige. No studies have demonstrated browning of typical human WAT depots, except for our recent studies. We have recently examined the subcutaneous (SC) WAT of humans and found a considerable ability to upregulate UCP1 and other mitochondrial genes in response to cold and to seasons, and we have demonstrated this phenomenon with human adipocytes in culture. The seasonal changes in WAT are of particular interest, since this indicates a physiologic response to colder weather, without provocative and unphysiologic experimental conditions. In addition, we found that obese humans with a high SC WAT macrophage burden do not upregulate SC WAT UCP1 as well, suggesting that adipose inflammation inhibits the increased thermogenic capacity of WAT. A number of immune-mediate functions are involved in this process. Based on these data, we propose the following hypotheses. Hypothesis 1. Repeated exposure to cold temperatures will amplify changes in human subcutaneous WAT beiging. These beiging effects are seen acutely, in response to seasons and involve an activation of immune mediators. Hypothesis 2. The beiging of SC WAT involves an acute increase in adipose tissue immune mediators, which may be a source of catecholamines that activate protein kinase A (PKA). This process is inhibited by ?-blockers in vivo. Hypothesis 3. Obese insulin resistant subjects are resistant to cold induced changes in WAT due to the proinflammatory milieu which inhibits local mediators of beiging. Hypothesis 4. Cold- and season-induced changes in SC WAT will lead to functional changes in the tissue, characterized by increased mitochondrial uncoupling, increased TG turnover (lipolysis) and increased resting metabolic rate. PUBLIC HEALTH: Obesity is closely linked with insulin resistance, diabetes and heart disease. Recent studies have focused on brown adipose tissue in humans, which may increase energy expenditure and help prevent obesity. This proposal examines the extent to which subcutaneous white adipose can become brown-like, or beige. We will determine whether this process is inhibited by the inflammatory state of obesity/metabolic syndrome, and we will characterize the effects of cold on adipose triglyceride turnover.

Public Health Relevance

Obesity is closely linked with insulin resistance, diabetes and heart disease. Recent studies have focused on brown adipose tissue in humans, which may increase energy expenditure and help prevent obesity. This proposal examines the extent to which subcutaneous white adipose can become brown-like, or beige. We will determine whether this process is inhibited by the inflammatory state of obesity/metabolic syndrome, and we will characterize the effects of cold on adipose triglyceride turnover.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK107646-01
Application #
9008664
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Haft, Carol R
Project Start
2015-09-21
Project End
2018-07-31
Budget Start
2015-09-21
Budget End
2016-07-31
Support Year
1
Fiscal Year
2015
Total Cost
$518,902
Indirect Cost
$170,761
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Finlin, Brian S; Memetimin, Hasiyet; Confides, Amy L et al. (2018) Human adipose beiging in response to cold and mirabegron. JCI Insight 3:
Lee, Scott J; Zea, Ryan; Kim, David H et al. (2018) CT texture features of liver parenchyma for predicting development of metastatic disease and overall survival in patients with colorectal cancer. Eur Radiol 28:1520-1528
Agrawal, Madhur; Kern, Philip A; Nikolajczyk, Barbara S (2017) The Immune System in Obesity: Developing Paradigms Amidst Inconvenient Truths. Curr Diab Rep 17:87
Finlin, Brian S; Zhu, Beibei; Confides, Amy L et al. (2017) Mast Cells Promote Seasonal White Adipose Beiging in Humans. Diabetes 66:1237-1246
Finlin, Brian S; Zhu, Beibei; Kok, Bernard P et al. (2017) The Influence of a KDT501, a Novel Isohumulone, on Adipocyte Function in Humans. Front Endocrinol (Lausanne) 8:255