Body composition-related functions: a problem-oriented approach to phenotyping

The objective of this study is to generate metabolic phenotypes based on structure–function relationships. In 459 healthy adults (54% females, 18 and 40 years old), we analyzed body composition by air-displacement densitometry (to assess fat mass, (FM) and fat-free mass (FFM)) and whole-body magnetic resonance imaging (to assess skeletal muscle mass (SMM) and masses of brain, heart, liver, kidneys, and subcutaneous (SAT) and visceral adipose tissue (VAT)), resting energy expenditure (REE) by indirect calorimetry, and plasma concentrations of insulin (Ins) and leptin (Lep). Three “functional body composition-derived phenotypes” (FBCPs) were derived: (1) REE on FFM-FBCP, (2) Lep on FM-FBCP, and (3) Ins on VAT-FBCP. Assuming that being within the ± 5% range of the respective regression lines reflects a “normal” structure–function relationship, three “normal” FBCPs were generated with prevalences of 9.0%, 5.1%, and 6.8%, respectively, of the study population. The three “FBCPs” did not overlap and were independent from each other. When compared with the two other FBCPs, the “Lep on FM-FBCP” was leanest, whereas the “REE on FFM-FBCP” had the highest BMI and SAT. Taking into account FFM composition, a hierarchical multi-level model is proposed with brain at level 1, the liver at level 2, and SMM and FM at level 3 with insulin coordinating the interplay between level 1 and 2, whereas variance in plasma insulin levels impacts energy and substrate metabolism in SMM and AT. Structure–function relationships can be used to generate FBCPs. Different FBCPs reflect different dimensions of normality (or health). This is evidence for the idea that there is no across the board “normal” state.