Leptin and the Intersection of Cardiovascular Disease, Metabolism, and Adipose Tissue

Sammanfattning: According to the World Health Organization, cardiovascular disease (CVD) is a group of disorders of the heart and blood vessels, and it is the leading cause of death worldwide. The risk factors for CVD are divided into two major classes: non-modifiable (age, gender, family history) and modifiable (including tobacco use, type 2 diabetes mellitus (T2DM), physical inactivity, unhealthy diet, abdominal obesity, high cholesterol, dyslipidemia, and stress). Because CVD is a major cause of mortality and morbidity, new and clinically useful biomarkers of cardiovascular risk are of essence. Since obesity is a risk factor for CVD, new ways to achieve weight loss are also important.  In this thesis, the focus is on leptin, a metabolic hormone with a pivotal function in the balance of appetite and satiety, and inducing weight loss. The adipose tissue releases leptin, with plasma levels of leptin reflecting the total adipose mass. Since it is related to both fat mass and cardiovascular risk, and is pro-inflammatory, it has been studied as a potential link between obesity, inflammation, hypertension, and vascular function.   In paper I, we aimed to see if repeated cold exposure increased metabolic rate and/or brown adipose tissue (BAT) volume in humans. Out of 28 recruited participants, we allocated 16 to expose themselves to cold for one hour every day for six weeks, while 12 were controls, instructed to avoid cold exposure. Through magnetic resonance imaging, we found that supra-clavicular BAT volume had increased in an on-treatment analysis of the cold exposure group.   In paper II, we used baseline data from 720 participants in “Cardiovascular Risk factors In Patients with Diabetes—a Prospective study in Primary care” (CARDIPP), all of whom had T2DM and were 55-66 years old at recruitment. We followed patients for incidence of ischemic heart disease (IHD) mortality and morbidity for 4-7 years, using the national Swedish Cause of Death and Hospitalization Registries. Our study showed that serum leptin levels related positively to the hazard ratio in both men and women, and predicted IHD independently of age, HbA1c, BMI, systolic blood pressure, and LDL/HDL-cholesterol ratio. This supports the use of serum leptin in patients with T2DM to add independent prognostic information in terms of IHD. When adding pulse wave velocity (PWV) and intima-media thickness to the model as markers of arterial stiffness, the finding of increased risk of IHD related to leptin levels remained statistically significant in men, but not in women.  In paper III, we aimed to discover novel associations between leptin and circulating proteins, to possibly link leptin with the development of CVD in patients with T2DM. Using proximity extension assay, we investigated associations between 88 plasma proteins in the CARDIPP population. We replicated the associations passing the significance threshold in patients with T2DM in an independent cohort and found that adipocyte fatty acid binding protein (A-FABP) was significantly associated with leptin in both cohorts, more so in men than women. A-FABP can be found in white adipocytes and macrophages, and some studies have identified it as a circulating biomarker for metabolic syndrome, T2DM, and cardiovascular events.  Finally, in paper IV, we analyzed data from 1 658 men and 1 678 women aged 50 to 65 when included in “The Swedish CardioPulmonary bioImage Study” (SCAPIS), focusing on leptin and its possible correlation with PWV. In bivariate correlations, we found log transformed leptin, and inflammatory markers IL-6, IL-18, and CRP, were all correlated in both men and women. In a multivariable linear regression, log transformed leptin correlated positively with PWV, independently of home blood pressure, smoking, non-HDL, BMI, T2DM, and IL-6, IL-18, and CRP. This suggests it may be possible to use leptin as a marker for PWV and arterial stiffness.In conclusion, this thesis provides new insights into leptin and its potential associations with other circulating proteins, and its connection to cardiovascular disease and inflammation, both in patients with T2DM and in healthy subjects. It also provides more insight into brown adipose tissue.