Schellekens_BLongum_Obesity_Stress_EBIOM_103176 (003)


H. Schellekens et al. / EBioMedicine xxx (xxxx) 103176

Fig. 6. B. longum APC1472 supplementation reduces fasting blood glucose levels and cortisol awakening response and increase active ghrelin in obese individuals. Fasting glucose and active ghrelin levels were measured at the beginning of the study (pre), after 6 weeks (mid) and after 12 weeks (post) of treatment. Cortisol awakening response was only assesed at the beginning of the stduy. All data are depicted of all 3 timepoints (A, C, E), as well as the change after 12 weeks compared to at the beginning of the study (B, D, F). Data are depicted as boxplot or scatter dot plot, where the dots depict individual datapoints, with n = 36 for the placebo group and n =46 for the B. longum APC1472 treatment group. * indicates a significant effect (* p <0.05, ** p <0.01).

the hypothalamic expression of the orexigenic peptides NPY and AgRP following B. longum APC1472 supplementation in mice. Both NPY and AgRP are orexigenic peptides that increase food intake when over- expressed or when administered centrally [77,78] and HFD-fed mice demonstrate, as expected, a decrease in both of these orexigenic pep- tides. In contrast, increased hypothalamic expression of anorexigenic peptides such as POMC and CART in response to a high-fat diet has been suggested as a natural feedback mechanism in order to maintain energy balance and body weight homeostasis [79,80]. The B. longum APC1472 was able to normalize the increased hypothalamic expression of the anorexigenic peptide CART in HFD-fed mice, suggesting a lower degree of energy imbalance and, therefore, a potential reduced meta- bolic dysfunction compared to HFD-fed mice. Moreover, CART is reg- ulated by leptin and its expression is positively correlated with leptin levels [81]. Therefore, the decreased leptin levels observed in the B. longum APC1472-HFD group also support the observed decreased CART expression. This highlights the potential of B. longum APC1472 to mod

ulate hypothalamic gene expression involved in energy homeostasis and appetite regulation, which warrants further investigation. In the human intervention study, no difference was observed in the primary outcome of BMI, even though the B. longum APC1472 supple- mentation was able to reduce body weight gain in HFD-induced obese mice. Similarly, no difference was observed in the supportive secondary outcome W/H ratio. This discrepancy might be explained by the fact that the majority of the human intervention cohort was non-diabetic, whereas the HFD-induced obese mice had a decreased glucose toler- ance, implying that host glucose metabolism may have been the main factor driving the reduction in body weight gain in the obese mice. It must also be noted that the treatment duration of the preclinical study was longer and, therefore, a longer treatment period in the human in- tervention study, or a higher treatment dosage, could have resulted in more significant differences and bigger effect-sizes. The 12-week dura- tion of the human study may have been too short of a time to see sig- nificant changes in BMI and W/H ration. In addition, using a mixture of

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