Testing the metabolic sink postulate: subcutaneous adipose tissue the protective depot
|Booth-Kalajian, Andrea Deborah, author
|Foster, Michelle, advisor
|Wier, Tiffany, committee member
|Melby, Chris, committee member
|Santangelo, Kelly, committee member
|Includes bibliographical references.
|Adipose tissue distribution and not body mass index is the major predictor of risk for obesity-related chronic disease. Specifically, central adiposity, intra-abdominal/visceral adipose tissue accumulation, is associated with adverse metabolic outcomes such as, but not limited to, insulin resistance syndrome, cardiovascular disease, and hypertension [1, 2]. Conversely, peripheral adiposity, subcutaneous/gluteofemoral adipose tissue accumulation, is considered protective against metabolic disease [3, 4]. It is proposed that the subcutaneous adipose depot functions as a "metabolic sink" to sequester and store lipid from circulation, preventing ectopic deposition. Therefore, an individual with high overall fat mass primarily located in the lower body subcutaneous adipose depots could be metabolically healthy while obese. While subcutaneous adipose tissue (SAT) has been associated with improved insulin sensitivity and lower risk of adverse metabolic outcomes, it has not been fully examined for exact mechanisms or causality. The broad goal of this proposal was to identify and understand how adipose tissue contributes to the development, progression, and possibly resistance to metabolic disease. The specific goal of this dissertation was to examine how SAT protects against metabolic dysregulation. One of the protective properties of LBSAT is its ability to expand and proliferate with new/healthy, lipid-filling adipocytes. We examined adipose tissue compensation following intra-abdominal fat removal and glucose homeostasis. Peroxisome proliferator-activated receptor-γ (PPARγ; an activator of adipogenesis) knockout mice and control mice received either Sham surgery or intra-abdominal lipectomy. The inability of cell proliferation following lipectomy in PPARγ knockout mice induces glucose intolerance. Control mice with intra-abdominal lipectomy had increases in peripheral adipose mass, cell size redistribution, and improved glucose tolerance. The Foster lab previously demonstrated that removal of LBSAT caused skeletal muscle, but not liver, lipid accumulation in standard CHOW and high fat diet (HFD) mice. Additionally, LBSAT removal resulted in deterioration of systemic glucose tolerance and muscle insulin sensitivity in HFD animals only. Hence, we proposed that muscle triglyceride deposition per se was not sufficient to explain systemic glucose intolerance. One purpose of this dissertation was to further examine the protective properties of SAT and to investigate the fundamental mechanisms that contribute to impairment of glucose tolerance. We sought to extend our previous research with a systematic approach. We hypothesized that SAT has a dose-dependent association with systemic glucose regulation and maintenance of insulin sensitivity in nearby muscle. Our focus here was to examine the relation between peripheral adipose tissue and glucose homeostasis. This was accomplished with progressive removal of adipose tissue: ~20%, 40%, or 80% of the total SAT. Mice fed HFD for 13 weeks exhibit a dose-dependent decline in systemic glucose tolerance. This was accompanied by a decline in femoral muscle insulin response in the basal state but not the insulin-stimulated state. Muscle triglycerides were significantly high in all surgery groups. Other contributing factors were eliminated, including circulating factors, adipocyte distribution and compensation, or liver triglycerides. Therefore, we have demonstrated a dose-response effect of progressive SAT removal on glucose intolerance and basal muscle insulin insensitivity. In addition to metabolic outcomes, we seek to identify a lipid signature that is linked to diet-induced impairments in glucose tolerance. Liquid chromatography and mass spectrometry (LCMS) were used to identify differential diet patterns of lipid species between CHOW and HFD. Mice that did not have fat removed and were fed a healthy chow diet have intramuscular triglycerides that are consistent with longer chain fatty acids (more carbons) and a higher degree of unsaturation (less hydrogens). They also have high abundance of phosphatidylserine and phosphatidylinositol. Diet-induced obesity is associated with femoral muscle lipids that include diacylglycerides and sphingomyelin. Overall, when examining the total lipid profile in muscle, healthy fats were more influential than unhealthy ones. In summary, inhibition of adipocyte proliferation results in glucose intolerance following intra-abdominal fat removal. Progressive subcutaneous fat removal results in a dose-dependent deterioration of systemic and muscle glucose homeostasis. Thus, peripheral fat does indeed serve as a "metabolic sink" that sequesters excess energy and preserves metabolic regulation. Muscle lipid accumulation per se is not detrimental to health, but the types of lipids that are stored should be considered.
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|Testing the metabolic sink postulate: subcutaneous adipose tissue the protective depot
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|Food Science and Human Nutrition
|Colorado State University
|Doctor of Philosophy (Ph.D.)