Molecular Changes During Weight Gain – Everyone Is DifferentWednesday, January 31, 2018
As one may well imagine, changes in body weight (up or down) can profoundly affect a vast number of hormonal and metabolic pathways.
Now, a team of researchers led by Brian Piening and colleagues, in a paper published in Cell Systems used a broad “omics” based approach to study what happens when people lose ore gain weight.
Specifically, the goal of this study was to:
(1) assemble a comprehensive map of the molecular changes in humans (in circulating blood as well as the microbiome) that occur over the course of a carefully controlled weight gain and their reversibility with weight loss; and
(2) determine whether inulin sensitive (IS) and insulin resistant (IR) individuals who are matched for degree of obesity demonstrate unique biomolecular signatures and/or pathway activation during similar weight gain.
The study included 23 carefully selected healthy participants with BMI 25–35 kg/m2, were studied. Samples were collected at baseline. They then underwent a 30-day weight gain period (average 2.8 kg), followed by an eucaloric diet for 7 days, at which point a second fasted sample of blood and stool was collected. Each participant then underwent a caloric-restricted diet under nutritionist supervision for a subsequent 60-day period designed to return each participant back to his/her initial baseline weight, at which point a third set of fasted samples of blood and stool were collected. A subset of participants returned for a follow-up sampling approximately 3 months after the end of the perturbation.Insulin resistance was assessed at baseline using a modified insulin suppression test.
The large-scale multi-omics assays performed at all time points on each participant included genomics, proteomics, metabolomics and microbiomics.
Despite some differences between the IS and IR group (particularly in differential regulation of inflammatory/immune response pathways), overall, molecular changes were dominated by inter-personal variation (i.e. changes within the same individual), which accounted for more than 90% of the observed variance in some cases (e.g., cytokines). The most striking changes with weight gain were in inflammation response pathways (despite the rather modest weight gain) and were (fortunately) reversed by weight loss.
As the authors note,
“Comparing the variation in cytokine levels between multiple baselines in a single individual versus across individuals, we observed a striking difference: for almost all cytokines, the within-individual coefficient of variation was under 20%, whereas the variation across individuals was 40%–60%. This shows that our baseline cytokine profiles are unique to the individual, a point that has significant implications for one-size-fits-all clinical cytokine assays for the detection and/or monitoring of disease.”
On the opposite side of the spectrum, proteomics and metabolomics measurements had a substantial unexplained component (30% and 35%, respectively), highlighting the presence of unaccounted factors (e.g., food, exercise, and other changing environmental factors) or a subject-specific reaction to the perturbation.
Notably, not all of the responses we observed were consistent across IR and IS participants.
“In particular, for the microbiome, we observed that the microbe A. muciniphila was weight gain responsive only in insulin-sensitive participants. The abundance of this particular microbe in IR individuals did not change across perturbations and was barely or not detectable in most IR individuals.”
Clearly, these findings highlight the fact that each individual is biochemically unique, which the authors note, makes a strong case for personalized analysis in medicine.
Perhaps more importantly for researchers, nearly all of the data are publicly available, enabling exploration of inter-omic relationships and alterations across a longitudinal perturbation, thus providing a valuable resource for the development and validation of bioinformatic tools and pipelines integrating disparate data types.