The heart is a highly metabolic organ that uses multiple energy sources to meet its demand for ATP production. Diurnal feeding-fasting cycles result in substrate availability fluctuations which, together with increased energetic demand during the active period, impose a need for rhythmic cardiac metabolism. The nuclear receptors REV-ERBα and β are essential repressive components of the molecular circadian clock and major regulators of metabolism. To investigate their role in the heart, here we generated mice with cardiomyocyte (CM)-specific deletion of both Rev-erb s, which died prematurely due to dilated cardiomyopathy. Loss of Rev-erbs markedly downregulated fatty acid oxidation genes prior to overt pathology, which was mediated by induction of the transcriptional repressor E4BP4, a direct target of cardiac REV-ERBs. E4BP4 directly controls circadian expression of Nampt and its biosynthetic product NAD + via distal cis -regulatory elements. Thus, REV-ERB-mediated E4BP4 repression is required for Nampt expression and NAD + production by the salvage pathway. Together, these results highlight the indispensable role of circadian REV-ERBs in cardiac gene expression, metabolic homeostasis and function.

Conflict of interest statement: M.A.L. is an advisory board member for Eli Lilly and Pfizer Inc., consultant to Novartis, and receives support from Pfizer for research not overlapping with the work reported here. M.R.H. has received research support, not used in the current studies, from investigator-initiated sponsored proposals from Eli Lilly & Co. and Boehringer-Ingelheim.

Circadian disruption, as occurs in shift work, is associated with metabolic diseases often attributed to a discordance between internal clocks and environmental timekeepers. REV-ERB nuclear receptors are key components of the molecular clock, but their specific role in the SCN master clock is unknown. We report here that mice lacking circadian REV-ERB nuclear receptors in the SCN maintain free-running locomotor and metabolic rhythms, but these rhythms are notably shortened by 3 hours. When housed under a 24-hour light:dark cycle and fed an obesogenic diet, these mice gained excess weight and accrued more liver fat than controls. These metabolic disturbances were corrected by matching environmental lighting to the shortened endogenous 21-hour clock period, which decreased food consumption. Thus, SCN REV-ERBs are not required for rhythmicity but determine the freerunning period length. Moreover, these results support the concept that dissonance between environmental conditions and endogenous time periods causes metabolic disruption.

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is a vital regulator of adipogenesis, insulin sensitivity, and lipid metabolism. Activation of PPARγ by antidiabetic thiazolidinediones (TZD) reverses insulin resistance but also leads to weight gain that limits the use of these drugs. There are two main PPARγ isoforms, but the specific functions of each are not established. Here we generated mouse lines in which endogenous PPARγ1 and PPARγ2 were epitope-tagged to interrogate isoform-specific genomic binding, and mice deficient in either PPARγ1 or PPARγ2 to assess isoform-specific gene regulation. Strikingly, although PPARγ1 and PPARγ2 contain identical DNA binding domains, we uncovered isoform-specific genomic binding sites in addition to shared sites. Moreover, PPARγ1 and PPARγ2 regulated a different set of genes in adipose tissue depots, suggesting distinct roles in adipocyte biology. Indeed, mice with selective deficiency of PPARγ1 maintained body temperature better than wild-type or PPARγ2-deficient mice. Most remarkably, although TZD treatment improved glucose tolerance in mice lacking either PPARγ1 or PPARγ2, the PPARγ1-deficient mice were protected from TZD-induced body weight gain compared with PPARγ2-deficient mice. Thus, PPARγ isoforms have specific and separable metabolic functions that may be targeted to improve therapy for insulin resistance and diabetes.

Obesity and other metabolic diseases are major public health issues that are particularly prevalent in industrialized societies where circadian rhythmicity is disturbed by shift work, jet lag, and/or social obligations. In mammals, daylight entrains the hypothalamic suprachiasmatic nucleus (SCN) to a ≈24 h cycle by initiating a transcription/translation feedback loop (TTFL) of molecular clock genes. The downstream impacts of the TTFL on clock-controlled genes allow the SCN to set the rhythm for the majority of physiological, metabolic, and behavioral processes. The TTFL, however, is ubiquitous and oscillates in tissues throughout the body. Tissues outside of the SCN are entrained to other signals, such as fed/fasting state, rather than light input. This system requires a considerable amount of biological flexibility as it functions to maintain homeostasis across varying conditions contained within a 24 h day. In the face of either circadian disruption (e.g., jet lag and shift work) or an obesity-induced decrease in metabolic flexibility, this finely tuned mechanism breaks down. Indeed, both human and rodent studies have found that obesity and metabolic disease develop when endogenous circadian pacing is at odds with the external cues. In the following review, we will delve into what is known on the circadian rhythmicity of nutrient metabolism and discuss obesity as a circadian disease.