Linking the Endocannabinoidome with Specific Metabolic Parameters in an Overweight and Insulin-Resistant Population: From Multivariate Exploratory Analysis to Univariate Analysis and Construction of Predictive Models

Abstract

The global obesity epidemic continues to rise worldwide. In this context, unraveling new interconnections between biological systems involved in obesity etiology is highly relevant. Dysregulation of the endocannabinoidome (eCBome) is associated with metabolic complications in obesity. This study aims at deciphering new associations between circulating endogenous bioactive lipids belonging to the eCBome and metabolic parameters in a population of overweight or obese individuals with metabolic syndrome. To this aim, we combined different multivariate exploratory analysis methods: canonical correlation analysis and principal component analysis, revealed associations between eCBome subsets, and metabolic parameters such as leptin, lipopolysaccharide-binding protein, and non-esterified fatty acids (NEFA). Subsequent construction of predictive regression models according to the linear combination of selected endocannabinoids demonstrates good prediction performance for NEFA. Descriptive approaches reveal the importance of specific circulating endocannabinoids and key related congeners to explain variance in the metabolic parameters in our cohort. Analysis of quartiles confirmed that these bioactive lipids were significantly higher in individuals characterized by important levels for aforementioned metabolic variables. In conclusion, by proposing a methodology for the exploration of large-scale data, our study offers additional evidence of the existence of an interplay between eCBome related-entities and metabolic parameters known to be altered in obesity.

Serum metabolite profiling yields insights into health promoting effect of A. muciniphila in human volunteers with a metabolic syndrome

“…Linear regression was then built between the metabolite acetoacetate and the first principal component summarizing the highest variance in acylcarnitine, as previously described. 89 …”

Exploring the endocannabinoidome in genetically obese (ob/ob) and diabetic (db/db) mice: Links with inflammation and gut microbiota

“…As previously described [28], correlation analysis between two data sets of variables were performed using the R package 'psych' (version 2.1.6). Based on the normality of the data distribution, a parametric test (i.e., Pearson) which assumes a normal distribution, or a non-parametric test (i.e., Spearman) which assumes a non-normal distribution of the data were used.…”

Endocannabinoids and the Gut-Brain Control of Food Intake and Obesity

“…Similar to rodents, humans prefer fatty and sweet foods when given a choice [65], and their consumption is associated with elevated levels of eCBs in blood [66]. Moreover, levels of eCBs are increased in blood in both human and rodent obesity [25,[67][68][69][70][71][72][73][74][75][76][77][78][79][80]; however, the impact that circulating eCBs may have on gut-brain function associated with food intake, dietary preferences, and obesity is unknown. Nonetheless, it is plausible that circulating eCBs act as a humoral signal that interacts with cannabinoid receptors along the gut-brain axis to facilitate these processes.…”

“…These investigations provide evidence of specific molecular and cellular mechanisms that underlie eCB-mediated gut-brain signaling, which may inform development of therapeutic strategies for the treatment of human obesity and related metabolic disorders. Indeed, human studies indicate that eCB levels are elevated in blood during consumption of palatable foods and in obesity [66][67][68][69][70][71][73][74][75][76][77]80,114]. CB 1 R antagonists were under development during the 2000s for the treatment of human obesity.…”