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Nina Geidenstam

Metabolomics of weight loss and weight maintenance in obese humans

The prevalence of obesity and obesity-related complications are increasing worldwide. Weight loss has shown to improve insulin sensitivity and decrease the risk of developing type 2 diabetes (T2D). Even so, little is known about how metabolites, other than glucoses are affected adter weight loss and weight maintenance treatment.

Impaired glucose tolerance (IGT) is a common trait of obesity and is studied during an oral glucose tolerance test (OGTT). In this these, we identified 16 district metabolite OGTT profiles (change from fasting, 30 and 120 min) that deviated from the glucose tolerant lean group. These deviations were grouped as, a delayed reduction in the levels of five fatty acids, increased levels at 30 min. of five amino acids (incl. isoleucine and leucine), and a blunted increase at 30 min. of six metabolites. When we followed up these obese individuals after weight loss and weight maintenance, roughly half of these metabolites improved towards the expected healthy profile. Specifically, enhanced suppression of aromatic amino acies (tyrosine and phenylalanine) was associated with decreased insulinogenic index after weight loss. On the contrare, the glucose-elicted suppression of four amino acids and three fatty acids improved after weight maintenance, aprallelling an improved glucose tolerance. This suggests that diet-induced weight loss followed by weight maintenance results in changes in matebolite OGTT profiles associated with either hepatic insulin sensitivity or peripheral glucose tolerance.

Obesity is associated with alteres levels of fasting circulating amino acids. We found that eight out of the 18 detected amino acids were associated with obesity, independently of age, sex, T2D and blood pressure. Six of these amino acids were improved efter weightmaintenance. From this, we created scors based on amino acid and risk factors at baseline that are either informative of the level of association to obesity or the potential benefit, or lack of benefit, by reducing the included amino acids to those that are expected to normalize with a weight loss and weight maintenance program.

Finally, we validated previous findings and further explored the data in a larger cohort at baseline and one year after participating in a non-surgical weight loss program. Changed levels in 30 metabolites were unique in those with a >-10% weight loss compared to those with <10% weight loss. In addition, we found weight loss to be associated with 13 baseline metabolit levels, and interestingly, many of these are common food additives. We also saw that the obesity predictive scores were modifable with weight loss.

The thesis adds to the understanding of metabolite alterations in obesity-driven
IGT and the benefits of weight loss followed by weight maintenance. Our findings suggest several metabolites that may be valuable to consider when evaluating who will benefit from weight loss treatments.

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