Consistent with a previous study (22
), our data reveal robust diurnal rhythmicity within human WAT in vivo. To date, limited data have been published concerning clock gene expression in this tissue. Because of difficulties in acquiring human tissue, some studies have measured clock gene expression in WAT collected at a single time point (18
), although it is clearly difficult to infer rhythmical changes from such a temporally limited dataset. An elegant compromise has been to culture explants of tissue taken at a single time point and then measure gene expression in fragments of the biopsies over a 24-h time course (17
). Although such studies highlight endogenous WAT rhythms, they do not reflect gene expression in vivo. Therefore, we measured gene expression in human tissue explants harvested across a whole 24-h cycle to provide in vivo human WAT rhythms.
Animal models suggest that obesity and type 2 diabetes reduce rhythm amplitude in murine WAT because lean C57BL/6J mice exhibit higher amplitude WAT rhythms than obese/diabetic KK and KK-Ay
). Other data revealed reduced amplitude rhythms in mice that became obese as a result of a high-fat diet (16
). However, Ando et al. (15
) compared mice with differing genetic backgrounds, which complicate interpretation of their data, and it is possible that dietary intervention could directly regulate gene expression rather than obesity per se.
In contrast to the above studies, we observed minimal differences between clock gene rhythms in human WAT. Interpretation of the minor difference in BMAL1
expression is not clear. Although murine Bmal1
has been implicated in the control of adipogenesis in vitro (23
), juvenile Bmal1−/−
mice develop adipose depots comparably to their wild-type littermates (24
). Furthermore, the similarity between gene expression profiles in lean individuals and those who were overweight with type 2 diabetes suggests that BMI is not the cause of the time × group interaction for BMAL1
in the overweight, nondiabetic individuals.
The similarity of gene expression profiles between our experimental groups may partly result from a lack of extreme phenotypic differences. Although there was not a large disparity in BMI between our groups, all participants fell into the current clinical guidelines for lean/healthy, obese, and type 2 diabetic individuals. Therefore, there was no effect of obesity or type 2 diabetes, per se, on human WAT rhythmicity. It remains possible that severely obese individuals may exhibit reduced amplitude WAT rhythmicity; however, interpretation of data from such individuals is complicated by various confounding factors, such as comorbidities associated with type 2 diabetes.
Another difference between our study and previous work (25
) is the high level of glycemic control in our participants. We specifically aimed to investigate the relationship between WAT rhythmicity, body weight, and presence of type 2 diabetes. Therefore, we eliminated as many additional factors as possible. Diurnal adipose gene expression may be modulated by the level of glycemic control and/or drugs taken by diabetic individuals. Alternatively, the association between metabolic state and WAT rhythmicity might vary between adipose depots. However, because of limitations of sampling and experimental group size, we could not directly address these possibilities in the current study.
The persistence of 24-h rhythms in WAT from patients with type 2 diabetes now suggests that the link between human circadian and metabolic physiology occurs outside of WAT, at least in the earlier stages of the disease.