S-Space College of Natural Sciences (자연과학대학) Program in Genetic Engineering (협동과정-유전공학전공) Theses (Ph.D. / Sc.D._협동과정-유전공학전공)
Characterization of gut microbiota and adipose tissues in the regulation of obesity-induced insulin resistance
비만으로부터 유도되는 인슐린 저항성 조절에 관여하는 장내미생물 및 지방조직의 역할 규명
- 자연과학대학 협동과정 유전공학전공
- Issue Date
- 서울대학교 대학원
- obesity; gut microbiota; GLP-1; fat-depot specificity; adipose tissue macrophage; gamma-aminobutyric acid
- 학위논문 (박사)-- 서울대학교 대학원 : 자연과학대학 협동과정 유전공학전공, 2018. 2. 김재범.
- Chronic energy imbalance leads to obesity, which has been considered as one of a critical risk factor for insulin resistance. Both of gut and adipose tissues have contributed to the regulation of whole body energy homeostasis. For example, small intestine controls the absorption of nutrients and the adipose tissues store extra energy. Recent findings have suggested that gut microbiota is closely linked to adiposity, insulin sensitivity, and glucose metabolism. Studies using germ-free (GF) mice, which are resistant to diet-induced obesity (DIO), have suggested that gut microbiota could play an essential role in the control of host energy homeostasis. Among various phyla in the gut, the abundance ratio of Firmicutes and Bacteroidetes, two major phyla, is altered in the progression of obesity. However, the contribution of Firmicutes and Bacteroidetes in the regulation of insulin resistance has not been
thoroughly understood in obesity.
Adipose tissue inflammation has been implicated in obesity. Among various fat depots, the mass of visceral adipose tissues is correlated with obesity-associated metabolic disorders. On the other hand, subcutaneous adipose tissue is recognized as a beneficial adipose tissue in the regulation of energy homeostasis. Although the physiological differences between visceral and subcutaneous adipose tissues have been documented in clinical and epidemiological studies, the underlying mechanisms elucidating the differential regulation of adipose tissue inflammation in different fat-depots remain unclear.
In chapter one, I have established the diet-induced obese (DIO) mice model which exhibited selective and significant reduction of Firmicutes and Bacteroidetes. Mice with altered gut microbiota ameliorated insulin resistance via increase of glucagon-like peptide 1 (GLP-1), a major gut hormone elevating insulin secretion and insulin sensitivity. Furthermore, alteration of the gut microbiota increased a bile product, taurocholic acid (TCA) which significantly activates GLP-1 secretion in human L-cell (NCI-H716). This study suggests that alteration of gut microbiota would act as an important regulator of obesity-induced insulin resistance. Thus, these findings enhance our understanding of how gut microbiota could interact with host energy homeostasis.
In chapter two, I have examined the underlying mechanisms of fat-depot specific inflammatory responses in obesity. It is of interest to observe that mouse inguinal adipose tissue (IAT) shows the apparent resistance of adipose tissue
macrophage (ATM) infiltration contrast to epididymal adipose tissue (EAT). In this study, I have shown that differential regulations of ATM infiltration between IAT and EAT are due to the intrinsic characteristics of two fat-depots. Gamma (γ)-aminobutyric acid (GABA) signaling pathway was shown to be differentially regulated in EAT and IAT. Pharmacological modulations of GABAB receptor signaling were solely efficient on ATM infiltration in IAT. Here, I have shown that adipose-derived stem cells (ADSCs) in IAT were responsive to GABA signaling. In accordance with anti-inflammatory roles of GABA in IAT, GABA treatment improved whole body insulin resistance, accompanied by attenuated adipose tissue inflammation in IAT. These data suggest that differential response to GABA between EAT and IAT would contribute to fat-depot specific characteristics in obesity-linked adipose tissue inflammation.
Taken together, I suggest that gut microbiota and IAT are crucial in the regulation of glucose metabolism in obesity. This study provides cellular and physiological understandings how obesity could be linked to systemic insulin resistance. Therefore, it appears that appropriate modulation of gut microbiota and adipose GABA responses might be a prominent strategy for amelioration of insulin resistance associated with various types of metabolic disorders.