Brown adipose tissue (BAT) catabolizes glucose and fatty acids to produce heat and thereby contributes to energy expenditure. Long-term high-fat diet (HFD) feeding results in so-called ‘whitening’ of BAT characterized by increased lipid deposition, mitochondrial dysfunction, and reduced fat oxidation. The aim of the current study was to unravel the rate and related mechanisms by which HFD induces BAT whitening and insulin resistance. Wild-type mice were fed a HFD for 0, 1, 3, or 7 days. Within 1 day of HFD, BAT weight and lipid content were increased. HFD also immediately reduced insulin-stimulated glucose uptake by BAT, indicating rapid induction of insulin resistance. This was accompanied by a tendency toward a reduced uptake of triglyceride-derived fatty acids by BAT. Mitochondrial mass and Ucp1 expression were unaltered, whereas after 3 days of HFD, markers of mitochondrial dynamics suggested induction of a more fused mitochondrial network. Additionally, HFD also increased macrophage markers in BAT after 3 days of HFD. Counterintuitively, the switch to HFD was accompanied by an acute rise in core body temperature. We showed that a single day of HFD feeding is sufficient to induce the first signs of whitening and insulin resistance in BAT, which reduces the uptake of glucose and triglyceride-derived fatty acids. BAT whitening and insulin resistance are likely sustained by reduced mitochondrial oxidation due to changes in mitochondrial dynamics and macrophage infiltration, respectively. Likely, the switch to HFD swiftly induces thermogenesis in other metabolic organs, which allows attenuation of BAT thermogenesis.

Objective Brown adipose tissue (BAT) displays a strong circadian rhythm in metabolic activity, but it is unclear how this rhythm is regulated. As circulating levels of corticosterone coincide with the rhythm of triglyceride-derived fatty acid (FA) uptake by BAT, we investigated whether corticosterone regulates BAT circadian rhythm. Methods Corticosterone levels were flattened by implanting mice with subcutaneous corticosterone-releasing pellets, resulting in constant circulating corticosterone levels. Results Flattened corticosterone rhythm caused a complete loss of circadian rhythm in triglyceride-derived fatty acid uptake by BAT. This effect was independent of glucocorticoid receptor expression in (brown) adipocytes and was not caused by deregulation of clock gene expression or overexposure to glucocorticoids, but rather seemed mediated by reduced sympathetic innervation of BAT. In a mouse model of hyperlipidemia and metabolic syndrome, long-term experimental flattening of corticosterone and thus rhythm in BAT function resulted in adiposity. Conclusions This study highlights that a physiological rhythm in glucocorticoids is an important regulator of BAT function and essential for the maintenance of metabolic health.

Objective Exercise has been shown to improve cardiometabolic health, yet neither the molecular connection nor the effects of exercise timing have been elucidated. The aim of this study was to investigate whether ad libitum or time‐restricted mild exercise reduces atherosclerosis development in atherosclerosis‐prone dyslipidemic APOE*3‐Leiden.CETP mice and whether mild exercise training in men with obesity affects lipoprotein levels. Methods Mice were group‐housed and subjected to ad libitum or time‐restricted (first or last 6 hours of the active phase) voluntary wheel running for 16 weeks while on a cholesterol‐rich diet, after which atherosclerosis development was assessed in the aortic root. Furthermore, nine men with obesity followed a 12‐week mild exercise training program. Lipoprotein levels were measured by nuclear magnetic resonance spectroscopy in plasma collected pre and post exercise training. Results Wheel running did not affect plasma lipid levels, uptake of triglyceride‐derived fatty acids by tissues, and aortic atherosclerotic lesion size or severity. Markers of training status were unaltered. Exercise training in men with obesity did not alter lipoprotein levels. Conclusions Mild exercise training does not reduce dyslipidemia or atherosclerosis development in APOE*3‐Leiden.CETP mice or affect lipoprotein levels in humans. Future research on the effects of (time‐restricted) exercise on atherosclerosis or lipid metabolism should consider more vigorous exercise protocols.

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The metabolic and inflammatory processes that are implicated in the development of cardiovascular diseases are under control of the biological clock. While skeletal muscle function exhibits circadian rhythms, it is unclear to what extent the beneficial health effects of exercise are restricted to unique time windows. We aimed to study whether the timing of exercise training differentially modulates the development of atherosclerosis and elucidate underlying mechanisms. We endurance‐trained atherosclerosis‐prone female APOE*3‐Leiden.CETP mice fed a Western‐type diet, a well‐established human‐like model for cardiometabolic diseases, for 1 h five times a week for 4 weeks either in their early or in their late active phase on a treadmill. We monitored metabolic parameters, the development of atherosclerotic lesions in the aortic root and assessed the composition of the gut microbiota. Late, but not early, exercise training reduced fat mass by 19% and the size of early‐stage atherosclerotic lesions by as much as 29% compared to sedentary animals. No correlation between cholesterol exposure and lesion size was evident, as no differences in plasma lipid levels were observed, but circulating levels of the pro‐inflammatory markers ICAM‐1 and VCAM‐1 were reduced with late exercise. Strikingly, we observed a time‐of‐day‐dependent effect of exercise training on the composition of the gut microbiota as only late training increased the abundance of gut bacteria producing short‐chain fatty acids with proposed anti‐inflammatory properties. Together, these findings indicate that timing is a critical factor to the beneficial anti‐atherosclerotic effects of exercise with a great potential to further optimize training recommendations for patients.