The circadian clock is a biological mechanism that dictates an array of rhythmic physiological processes. Virtually all cells contain a functional clock whose disruption results in altered timekeeping and detrimental systemic effects, including cancer. Recent advances have connected genetic disruption of the clock with multiple transcriptional and signaling networks controlling tumor initiation and progression. An additional feature of this circadian control relies on cellular metabolism, both within the tumor microenvironment and the organism systemically. A discussion of major advances related to cancer metabolism and the circadian clock will be outlined, including new efforts related to metabolic flux of transformed cells, metabolic heterogeneity of tumors, and the implications of circadian control of these pathways.

Metabolic rewiring is a hallmark feature prevalent in cancer cells as well as insulin resistance (IR) associated with diet-induced obesity (DIO). For instance, tumor metabolism shifts towards an enhanced glycolytic state even under aerobic conditions. In contrast, DIO triggers lipid-induced IR by impairing insulin signaling and reducing insulin-stimulated glucose uptake. Based on physiological differences in systemic metabolism, we used a breath analysis approach to discriminate between different pathological states using glucose oxidation as a readout. We assessed glucose utilization in lung cancer-induced cachexia and DIO mouse models using a U-¹³C glucose tracer and stable isotope sensors integrated into an indirect calorimetry system. Our data showed increased ¹³CO₂ expired by tumor-bearing (TB) mice and a reduction in exhaled ¹³CO₂ in the DIO model. Taken together, our findings illustrate high glucose uptake and consumption in TB animals and decreased glucose uptake and oxidation in obese mice with an IR phenotype. Our work has important translational implications for the utility of stable isotopes in breath-based detection of glucose homeostasis in models of lung cancer progression and DIO.

Lung adenocarcinoma is associated with cachexia, which manifests as an inflammatory response that causes wasting of adipose tissue and skeletal muscle. We previously reported that lung tumor-bearing (TB) mice exhibit alterations in inflammatory and hormonal signaling that deregulate circadian pathways governing glucose and lipid metabolism in the liver. Here, we define the molecular mechanism of how de novo glucose production in the liver is enhanced in a model of lung adenocarcinoma. We found that elevation of serum glucagon levels stimulates cyclic adenosine monophosphate production and activates hepatic protein kinase A (PKA) signaling in TB mice. In turn, we found that PKA targets and destabilizes the circadian protein REV-ERBα, a negative transcriptional regulator of gluconeogenic genes, resulting in heightened de novo glucose production. Together, we identified that glucagon-activated PKA signaling regulates REV-ERBα stability to control hepatic glucose production in a model of lung cancer-associated cachexia.

Ceramide-induced mitochondrial fission drives high-fat diet (HFD)-induced obesity. However, molecules targeting mitochondrial dynamics have shown limited benefits in murine obesity models. Here, we reveal that these compounds are either unable to block ceramide-induced mitochondrial fission or require extended incubation periods to be effective. In contrast, targeting endolysosomal trafficking events important for mitochondrial fission rapidly and robustly prevented ceramide-induced disruptions in mitochondrial form and function. By simultaneously inhibiting ARF6- and PIKfyve-dependent trafficking events, the synthetic sphingolipid SH-BC-893 blocked palmitate- and ceramide-induced mitochondrial fission, preserved mitochondrial function, and prevented ER stress in vitro. Similar benefits were observed in the tissues of HFD-fed mice. Within 4 h of oral administration, SH-BC-893 normalized mitochondrial morphology in the livers and brains of HFD-fed mice, improved mitochondrial function in white adipose tissue, and corrected aberrant plasma leptin and adiponectin levels. As an interventional agent, SH-BC-893 restored normal body weight, glucose disposal, and hepatic lipid levels in mice consuming a HFD. In sum, the sphingolipid analog SH-BC-893 robustly and acutely blocks ceramide-induced mitochondrial dysfunction, correcting diet-induced obesity and its metabolic sequelae.

Skin epidermis constitutes the outer permeability barrier that protects the body from dehydration, heat loss, and myriad external assaults. Mechanisms that maintain barrier integrity in constantly challenged adult skin and how epidermal dysregulation shapes the local immune microenvironment and whole-body metabolism remain poorly understood. Here, we demonstrate that inducible and simultaneous ablation of transcription factor-encoding Ovol1 and Ovol2 in adult epidermis results in barrier dysregulation through impacting epithelial-mesenchymal plasticity and inflammatory gene expression. We find that aberrant skin immune activation then ensues, featuring Langerhans cell mobilization and T cell responses, and leading to elevated levels of secreted inflammatory factors in circulation. Finally, we identify failure to gain body weight and accumulate body fat as long-term consequences of epidermal-specific Ovol1/2 loss and show that these global metabolic changes along with the skin barrier/immune defects are partially rescued by immunosuppressant dexamethasone. Collectively, our study reveals key regulators of adult barrier maintenance and suggests a causal connection between epidermal dysregulation and whole-body metabolism that is in part mediated through aberrant immune activation.

Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by the concerted activity of these clocks is associated with metabolic disease. Here we tested the interactions between clocks in two critical components of organismal metabolism, liver and skeletal muscle, by rescuing clock function either in each organ separately or in both organs simultaneously in otherwise clock-less mice. Experiments showed that individual clocks are partially sufficient for tissue glucose metabolism, yet the connections between both tissue clocks coupled to daily feeding rhythms support systemic glucose tolerance. This synergy relies in part on local transcriptional control of the glucose machinery, feeding-responsive signals such as insulin, and metabolic cycles that connect the muscle and liver. We posit that spatiotemporal mechanisms of muscle and liver play an essential role in the maintenance of systemic glucose homeostasis and that disrupting this diurnal coordination can contribute to metabolic disease.

An alarming rise in young onset colorectal cancer (CRC) has been reported; however, the underlying molecular mechanism remains undefined. Suspected risk factors of young onset CRC include environmental aspects, such as lifestyle and dietary factors, which are known to affect the circadian clock. We find that both genetic disruption and environmental disruption of the circadian clock accelerate Apc-driven CRC pathogenesis in vivo. Using an intestinal organoid model, we demonstrate that clock disruption promotes transformation by driving Apc loss of heterozygosity, which hyperactivates Wnt signaling. This up-regulates c-Myc, a known Wnt target, which drives heightened glycolytic metabolism. Using patient-derived organoids, we show that circadian rhythms are lost in human tumors. Last, we identify that variance between core clock and Wnt pathway genes significantly predicts the survival of patients with CRC. Overall, our findings demonstrate a previously unidentified mechanistic link between clock disruption and CRC, which has important implications for young onset cancer prevention.