Chronic inadequate sleep is associated with increased risk of cardiometabolic diseases. The mechanisms involved are poorly understood but involve changes in insulin sensitivity, including within adipose tissue. The aim of this study was to assess the effects of sleep restriction on nonesterified fatty acid (NEFA) suppression profiles in response to an intravenous glucose tolerance test (IVGTT) and to assess whether 2 nights of recovery sleep (a “weekend”) is sufficient to restore metabolic health. We hypothesized that sleep restriction impairs both glucose and lipid metabolism, specifically adipocyte insulin sensitivity, and the dynamic lipemic response of adipocyte NEFA release during an IVGTT. Fifteen healthy men completed an inpatient study of 3 baseline nights (10 h of time in bed/night), followed by 5 nights of 5 h of time in bed/night and 2 recovery nights (10 h of time in bed/night). IVGTTs were performed on the final day of each condition. Reductions in insulin sensitivity without a compensatory change in acute insulin response to glucose were consistent with prior studies (insulin sensitivity P = 0.002; acute insulin response to glucose P = 0.23). The disposition index was suppressed by sleep restriction and did not recover after recovery sleep ( P < 0.0001 and P = 0.01, respectively). Fasting NEFAs were not different from baseline in either the restriction or recovery conditions. NEFA rebound was significantly suppressed by sleep restriction ( P = 0.01) but returned to baseline values after recovery sleep. Our study indicates that sleep restriction impacts NEFA metabolism and demonstrates that 2 nights of recovery sleep may not be adequate to restore glycemic health.

Supplementary key words triglycerides • nutrition • lipolysis and fatty acid metabolism • diet and dietary lipids • fatty acid • insulin resistance • inflammation • hormones • glucose According to the Centers for Disease Control and Prevention, one in three US adults sleeps fewer than 7 h per night, increasing their risk of obesity and for risk of developing CVD, type 2 diabetes, and earlier mortality, among other comorbidities (1-4). The mechanisms by which chronic insufficient sleep increases cardiometabolic disease risk are poorly understood, but results from carefully controlled laboratory studies demonstrate that sleep restriction simultaneously increases orexigenic hormonal signaling and impairs glucose metabolic functioning (5, 6). Furthermore, there is mounting evidence that adipocyte insulin sensitivity and function are impaired by sleep restriction resulting in aberrantly elevated overnight and early morning NEFAs (7-10). Adipocytes are a key integrator of systemic metabolism, absorbing and storing excess energy postprandially and releasing stored fatty acids as needed to meet the energy requirements of the body (11). Adipocytes respond to the postprandial increase in insulin by suppressing intracellular TG lipolysis and by increasing extracellular lipolysis by transporting LPL from intracellular vesicles to the surface Abstract Chronic sleep restriction, or inadequate sleep, is associated with increased risk of cardiometabolic disease. Laboratory studies demonstrate that sleep restriction causes impaired whole-body insulin sensitivity and glucose disposal. Evidence suggests that inadequate sleep also impairs adipose tissue insulin sensitivity and the NEFA rebound during intravenous glucose tolerance tests, yet no studies have examined the effects of sleep restriction on high-fat meal lipemia. We assessed the effect of 5 h time in bed (TIB) per night for four consecutive nights on postprandial lipemia following a standardized high-fat dinner (HFD). Furthermore, we assessed whether one night of recovery sleep (10 h TIB) was sufficient to restore postprandial metabolism to baseline. We found that postprandial triglyceride (TG) area under the curve was suppressed by sleep restriction (P = 0.01), but returned to baseline values following one night of recovery. Sleep restriction decreased NEFAs throughout the HFD (P = 0.02) and NEFAs remained suppressed in the recovery condition (P = 0.04). Sleep restriction also decreased participant-reported fullness or satiety (P = 0.03), and decreased postprandial interleukin-6 (P < 0.01). Our findings indicate that four nights of 5 h TIB per night impair postprandial lipemia and that one night of recovery sleep may be adequate for recovery of TG metabolism, but not for markers of adipocyte function.

The effects of sleep restriction on subjective alertness, motivation, and effort vary among individuals and may explain interindividual differences in attention during sleep restriction. We investigated whether individuals with a greater decrease in subjective alertness or motivation, or a greater increase in subjective effort (versus other participants), demonstrated poorer attention when sleep restricted. Participants and Methods: Fifteen healthy men (M±SD, 22.3±2.8 years) completed a study with three nights of 10-hour time in bed (baseline), five nights of 5-hour time in bed (sleep restriction), and two nights of 10-hour time in bed (recovery). Participants completed a 10-minute psychomotor vigilance task (PVT) of sustained attention and rated alertness, motivation, and effort every two hours during wake (range: 3-9 administrations on a given day). Analyses examined performance across the study (first two days excluded) moderated by per-participant change in subjective alertness, motivation, or effort from baseline to sleep restriction. For significant interactions, we investigated the effect of study day 2 (day*day) on the outcome at low (mean−1 SD) and high (mean+1 SD) levels of the moderator (N = 15, all analyses). Results: False starts increased across sleep restriction in participants who reported lower (mean−1 SD) but not preserved (mean+1 SD) motivation during sleep restriction. Lapses increased across sleep restriction regardless of change in subjective motivation, with a more pronounced increase in participants who reported lower versus preserved motivation. Lapses increased across sleep restriction in participants who reported higher (mean+1 SD) but not preserved (mean−1 SD) effort during sleep restriction. Change in subjective alertness did not moderate the effects of sleep restriction on attention. Conclusion: Vigilance declines during sleep restriction regardless of change in subjective alertness or motivation, but individuals with reduced motivation exhibit poorer inhibition. Individuals with preserved subjective alertness still perform poorly during sleep restriction, while those reporting additional effort demonstrate impaired vigilance.

In rodents, susceptibility to diet-induced obesity requires microglial activation, but the molecular components of this pathway remain incompletely defined. Prostaglandin E2 (PGE2) levels increase in the mediobasal hypothalamus during high fat diet (HFD) feeding, and the PGE2 receptor EP4 regulates microglial activation state and phagocytic activity, suggesting a potential role for microglial EP4 signaling in obesity pathogenesis. To test the role of microglial EP4 in energy balance regulation, we analyzed the metabolic phenotype in a cell-specific EP4 knockout mouse model. Microglial EP4 deletion markedly reduced weight gain and food intake in response to HFD feeding. In correspondence with this lean phenotype, insulin sensitivity was also improved in the HFD-fed MG-EP4 KO mice though glucose tolerance remained surprisingly unaffected. Mechanistically, EP4-deficient microglia showed an attenuated phagocytic state marked by reduced CD68 expression and fewer contacts with POMC neuron processes. These cellular changes observed in the microglial EP4 knockout mice corresponded with an increased density of POMC neurites extending into the paraventricular nucleus. These findings reveal that microglial EP4 signaling promotes body weight gain and insulin resistance during HFD feeding. Furthermore, the data suggest that curbing microglial phagocytic function may preserve POMC cytoarchitecture and PVN input to limit overconsumption during diet-induced obesity.

BackgroundIn rodents, susceptibility to diet-induced obesity requires microglial activation, but the molecular components of this pathway remain incompletely defined. Prostaglandin E2 (PGE2) levels increase in the mediobasal hypothalamus during high fat diet (HFD) feeding, and the PGE2 receptor EP4 regulates microglial activation state and phagocytic activity, suggesting a potential role for microglial EP4 signaling in obesity pathogenesis.MethodMetabolic phenotyping, as assessed by body weight, energy expenditure, glucose, and insulin tolerance, was performed in microglia-specific EP4 knockout (MG-EP4 KO) mice and littermate controls on HFD. Morphological and gene expression analysis of microglia, and a histological survey of microglia-neuron interactions in the arcuate nucleus was performed. Phagocytosis was assessed using in vivo and in vitro pharmacological techniques.ResultsMicroglial EP4 deletion markedly reduced weight gain and food intake in response to HFD feeding. In correspondence with this lean phenotype, insulin sensitivity was also improved in the HFD-fed MG-EP4 KO mice though glucose tolerance remained surprisingly unaffected. Mechanistically, EP4-deficient microglia showed an attenuated phagocytic state marked by reduced CD68 expression and fewer contacts with POMC neuron soma and processes. These cellular changes observed in the microglial EP4 knockout mice corresponded with an increased density of POMC neurites extending into the paraventricular nucleus.ConclusionThese findings reveal that microglial EP4 signaling promotes body weight gain and insulin resistance during HFD feeding. Furthermore, the data suggest that curbing microglial phagocytic function may preserve POMC cytoarchitecture and PVN input to limit overconsumption during diet-induced obesity.