Interrogating biomarkers for, and the pathophysiological mechanisms of, obesity-related complications

Obesity is now recognised as a chronic low-grade inflammatory disease, contributing to multisystem complications including chronic kidney disease (CKD), type 2 diabetes (T2D), and non-alcoholic fatty liver disease (NAFLD). Metabolic bariatric surgery (MBS) is regarded as the gold standard for patients with a BMI of 35 or higher, while recent pharmacotherapy advances have revolutionised obesity treatment. However, current obesity measurements remain suboptimal in guiding decision-making for personalized obesity treatment and obesity-related complications risk stratification. Additionally, the intricate physiological mechanisms behind the beneficial and comparative effects of MBS (gastric bypass (GB) and sleeve gastrectomy (SG)) and pharmacotherapy (liraglutide (1.8mg) ± empagliflozin (25mg)) in patients with CKD, T2D, and less severe class III obesity remains inadequately elucidated. In Chapter 2, we employed discovery proteomics to identify novel, modifiable biomarkers linked to the triad of CKD, T2D, and obesity, and compare the effects of surgical or pharmacotherapy-induced weight-loss on serum protein levels, and examine the correlation to improvements in measures of cardiometabolic health and weight-loss over 12 months. GB displayed superior outcomes in terms of improving cardiometabolic health biomarkers, reducing systemic nflammation and improving reverse cholesterol transport proteins, as compared to other treatment modalities. C3 emerged as the sole inflammatory protein consistently exhibiting downregulation across all groups, irrespective of the treatment modalities. Within the spectrum of apolipoproteins, both APOC4-APOC2 and APOD exhibited significant upregulation in post-surgical interventions (SB&GB); while APOA4 demonstrated significant upregulation following both GB surgery and pharmacotherapy, in comparison to the baseline measurements. In tandem with the obesity pandemic, NAFLD is on the rise, highlighting its emergence as a significant pathological concern. Currently, there are no approved treatments available, and a significant challenge exists in translating findings from preclinical animal studies into relevant applications for humans. In Chapter 3, we aim to establish a cell culture model that recapitulates the NAFLD-to-NASH transition by manipulating the metabolic fuel availability (glucose ± palmitic acid (PA; to emulate NAFLD) ± inflammatory stimulus (IL-1β; to emulate NASH) to further examine global alterations in the cellular proteome. Our findings indicated that the introduction of additional stressors induced a progressive inflammatory response. Excessive availability of glucose (i.e., 25mM) upregulated LXR/RXR activation, acute phase response signalling, glycolysis, and de novo lipogenesis. In the presence of hyperglycaemic conditions, we found heightened expressions of both C3 and APOB, coupled with diminished levels of LDLR. This underscores the significant contribution of hyperglycaemic conditions to both inflammation and perturbed lipid metabolism. IL-1β addition to the PA-enriched microenvironment triggers mitochondrial dysfunction, characteristic of NASH progression. These findings offer fundamental insights into the pathophysiology of NAFLD, making a notable contribution to the ongoing endeavours to comprehend the influence of metabolic and inflammatory stressors inherent to the disease microenvironment on protein networks within the human hepatocyte model. Collectively, it is evident that the evolution of proteomic technology plays a pivotal role in developing precise biomarkers for effectively stratifying obesity and its related complications. In particular, it is of significance that the potent reduction of C3 through obesity intervention and its elevation in hepatocytes treated with 25mM glucose ± IL-1β holds promise for shedding light on obesity mechanisms understanding and the exploration of fresh avenues in biomarker development.