Background & Aim of the Thesis: Obesity increases the likelihood of developing the metabolic syndrome (MetSyn), a cluster of risk factors that increase the chance of debilitating or even fatal cardiometabolic diseases (CMDs). Today, obesity disables and kills, in large part, because of the associated cardiovascular complications. CMD pathogenesis is complex, in that it involves several pathways of inter-organ communication. While there is a multiplicity of target organs and pathways, few have panned out into successful, druggable, treatment avenues. A notable exception is the glucagon-like peptide-1 (GLP-1) receptor agonist drug class, which, building on solid preclinical research, resulted in the development of a very successful treatment targeting obesity and its associated CMDs. The key to this success was the identification of an intra-organ crosstalk signaling node, GLP-1, which has relevant activity in all pathologies of interest. Building on this great example of success this thesis aims to identify other key intra-organ crosstalk signaling nodes relevant in obesity, MetSyn and CMDs which have the potential to lead to new or improved therapies. Methods Employed: We employ three models throughout this thesis: patient clinical trials, rodent models, and in-vitro cell models. In order to identify relevant crosstalk nodes in humans, we analyze blood samples from patients that underwent a hypocaloric diet lifestyle weight loss intervention, and two different cohorts of patients that underwent bariatric surgeries. We use bariatric surgery as a model for the recovery of healthy cardiovascular function after metabolic disease, and compare it to diet patients, who despite incurring significant weight loss, do not recover cardiovascular function to the same extent as post-bariatric patients. Further, we use a rat model of Roux-en-Y gastric bypass (RYGB) and healthy animals to study the molecular mechanisms involved in cardiovascular function recovery. We also use primary human aortic endothelial cell as our main \emph{in-vitro} model to assess the specific molecular pathways targeted in the endothelium, the gatekeeper of vascular function. Results Highlights: Using a translational approach, we identify three potential crosstalk nodes that may influence CMD severity and recovery. Chapter 1 is a review we published in 2020 and provides a general introduction to a key signaling node in this thesis: high-density lipoproteins (HDLs). In Chapter 2, we look into the increase in bile acids (BAs) in the circulation and on HDLs after RYGB. We identify that the post-surgical improvement in HDL’s endothelial anti-apoptosis function correlates to the HDL content of cholic acid (CA). Through exogenous loading of diseased HDL with CA, we are able to partially restore its anti-apoptotic function, via the inhibition of endothelial caspase-3 activity. These data show a key synergism between HDL and BA in endothelial signaling and may open the door for interesting therapeutic developments. In Chapter 3, we further explore HDL’s role post-bariatric, looking at a cohort of patients that underwent both RYGB and biliopancreatic diversion (BPD). We see that HDL’s functional improvements are maintained 5-years post-surgically, as well as the improvements in glucose control. Further, we are able to show that there is an association between the detailed lipidome of HDL and these improvements, potentially providing further mechanistic explanations for the success of bariatric surgeries in treating MetSyn and CMDs. Finally, we show that RYGB and BPD alter the lipidome of HDL in very different ways, which may account for their differential effects. These data may suggest that some bariatric procedures could be optimized, allowing us to compound the positive effects of all surgeries in a single procedure. In Chapter 4, we explore the final signaling node identified herein, trimethylamine N-oxide (TMAO), a gut metabolite that is thought to be particularly detrimental to cardiovascular health. Interestingly, we observe a significant increase in circulating TMAO after RYGB in patients and rats, but not after hypocaloric diet. This is in spite of a well-documented improvement in endothelial function post-RYGB. Based on this, we explored the role of TMAO in healthy rodents and cell models, to parse the direct effects of TMAO on endothelial function. We concluded this study by demonstrating that, in healthy conditions, acute TMAO exposure/treatment is neutral towards endothelial function. All chapters are either reprints of accepted manuscripts (Chapter 1) or preprints of manuscripts that will be submitted shortly (Chapters 2, 3 & 4). In Chapter 5, I broaden my view from the three individual manuscripts and discuss the data and its implications together. Finally, in the appendix of this thesis, I present some notable collaborations that have resulted in publications, another review I have written, a poster and grant award I was given and my current CV. Conclusion: To briefly conclude, this thesis presents three stories which identified and discusses \emph{two key signaling nodes relevant in the resorption of cardiovascular disease after bariatric surgeries. HDLs and BAs have emerged as important whole-body crosstalk signaling nodes that warrant further investigation, and, potentially, may lead to new and exciting therapeutic applications. TMAO on the other hand, should be re-considered as a causal agent in cardiovascular disease and may potentially just be a neutral bystander.