Examining the metabolic, physiologic and chronobiologic effects of Western diet-induced obesity in a mouse model

Abstract

Obesity is a major public health concern that can result from consuming a Western diet (WD), characterized by a diet high in fat and sugar, including sugar sweetened beverages. A proposed treatment for WD-induced obesity is time-restricted feeding (TRF), which restricts consumption of food to specific times of the 24-hour cycle. TRF improves metabolic health by aligning the timing of food intake with the circadian rhythms of nutrient metabolism. Circadian rhythms are behavioral and physiological patterns that occur every 24 hours. In mammals, circadian rhythms are entrained to light:dark cycles by photic input to the master circadian regulator, the suprachiasmatic nucleus (SCN). Every cell in the body, however, possesses a set of core clock genes and in tissues such as the liver and adipose, rhythmic expression of these genes may be desynchronized from the SCN by fed/fasting cycles. WD feeding, in particular, has been shown to result in significant desynchronization of peripheral clocks from the SCN. TRF shows great promise to prevent obesity and the development of chronic disease by resynchronizing the periphery with the SCN. However, the ability of TRF to reverse metabolic changes in animal models of WD-induced obesity is not known. Moreover, the exact role of timing liquid sugar intake, independent of timing solid food intake, on the development of WD-induced obesity remains to be determined. The liver is not only one of the most sensitive organs to WD-induced dysfunction, but it is particularly responsive to metabolic improvements after TRF. The hippocampus is also incredibly sensitive to the metabolic disruptions resulting from WD feeding. Until now, the impact of WD feeding and obesity on hippocampal rhythmicity has yet to be examined. Thus, the overarching objective of the presented works was to determine the role of chronobiology in the metabolic, physiologic and behavioral effects of WD-induced obesity. First, we found that TRF of a WD consisting of a 45% kcal/g high-fat diet supplemented with a 4% fructose/sucrose solution as drinking water did not result in significant weight loss. However, markers of non-alcoholic fatty liver disease (NAFLD) and glucose and insulin intolerance were improved by TRF in the WD group. Next, we examined metabolic and physiologic parameters in mice given liquid sugar at various intervals over 24-hours. The control (Con) group received tap water, the ad libitum fructose-glucose (ALFG) group received ad libitum access to a 12% fructose/glucose solution (FGS) and the early fructose-glucose (EFG) and late fructose-glucose (LFG) groups received the FGS during the first and last six hours of the active period, respectively. Each group was given free access to chow. The ALFG group exhibited elevated body weight, adipose tissue weight and increased markers of NAFLD. The ALFG group consumed more calories than the other groups during zeitgeber time (ZT) 6-11, indicating that this window may be critical in the promotion of weight gain from liquid sugar consumption. Interestingly, the EFG group exhibited improved metabolic flexibility and insulin tolerance. Finally, WD-induced obesity induced significant alterations in the rhythmicity of hippocampal core clock genes. Furthermore, the expression pattern of genes implicated in Alzheimer’s disease (AD) risk and synaptic function were significantly altered in the WD group and in vivo hippocampal memory was disrupted in a task- and time-dependent manner. Overall, the works herein implicate rhythm disruptions as a common link among the metabolic, physiologic and behavioral effects of WD-induced obesity.