(TG). We previously demonstrated that mice exposed to chronic IH develop elevated TG. We now hypothesize that a single exposure to acute hypoxia also increases TG due to the stimulation of free fatty acid (FFA) mobilization from white adipose tissue (WAT), resulting in increased hepatic TG synthesis and secretion. Male C57BL6/J mice were exposed to FiO2 ϭ 0.21, 0.17, 0.14, 0.10, or 0.07 for 6 h followed by assessment of plasma and liver TG, glucose, FFA, ketones, glycerol, and catecholamines. Hypoxia dosedependently increased plasma TG, with levels peaking at FiO2 ϭ 0.07. Hepatic TG levels also increased with hypoxia, peaking at FiO2 ϭ 0.10. Plasma catecholamines also increased inversely with FiO2. Plasma ketones, glycerol, and FFA levels were more variable, with different degrees of hypoxia inducing WAT lipolysis and ketosis. FiO2 ϭ 0.10 exposure stimulated WAT lipolysis but decreased the rate of hepatic TG secretion. This degree of hypoxia rapidly and reversibly delayed TG clearance while decreasing [ 3 H]triolein-labeled Intralipid uptake in brown adipose tissue and WAT. Hypoxia decreased adipose tissue lipoprotein lipase (LPL) activity in brown adipose tissue and WAT. In addition, hypoxia decreased the transcription of LPL, peroxisome proliferator-activated receptor-␥, and fatty acid transporter CD36. We conclude that acute hypoxia increases plasma TG due to decreased tissue uptake, not increased hepatic TG secretion.lipolysis; lipases; adipose; thermoregulation; metabolism OBSTRUCTIVE SLEEP APNEA (OSA) causes recurrent episodes of asphyxia and intermittent hypoxia (IH) during sleep. Several studies reveal an association between OSA and elevated circulating triglycerides (TG) (16). In some cases, the severity of hypoxia during sleep correlates with the magnitude of increased TG (18, 48). Furthermore, therapy for OSA with continuous positive airway pressure (CPAP) decreases fasting (61) and postprandial TG levels (51); yet, the mechanisms by which OSA affects TG levels are unclear. One possibility is that repetitive IH increases TG levels. Our laboratory has simulated hypoxic desaturations of OSA in mice, exposing them to diurnal IH (60 desaturations/h, 12 h/day). After chronic IH exposure, mice exhibited ϳ40% increases in plasma TG after 5 days (40), with similar elevations persisting after 4 and 12 wk of ongoing IH exposure (32). We have also shown that chronic IH increases TG via two major mechanisms, increased hepatic secretion (39) and decreased lipoprotein clearance (17).Two important questions have not been addressed by chronic IH experiments. First, is chronicity of hypoxia necessary to affect lipid metabolism? Second, is intermittency a necessary factor? Short-term sustained hypoxia in humans (2, 19, 71) and animals (43, 47) also induces hypertriglyceridemia. Surprisingly, no studies have systematically examined the mechanisms by which acute hypoxic exposures elevate TG. It is conceivable that acute sustained hypoxia increases TG via the same mechanisms that we have described for chronic IH. We ther...

There is currently no direct, facile method to determine total-body skeletal muscle mass for the diagnosis and treatment of skeletal muscle wasting conditions such as sarcopenia, cachexia, and disuse. We tested in rats the hypothesis that the enrichment of creatinine-( methyl-d3) (D3-creatinine) in urine after a defined oral tracer dose of D3-creatine can be used to determine creatine pool size and skeletal muscle mass. We determined 1) an oral tracer dose of D3-creatine that was completely bioavailable with minimal urinary spillage and sufficient enrichment in the body creatine pool for detection of D3-creatine in muscle and D3-creatinine in urine, and 2) the time to isotopic steady state. We used cross-sectional studies to compare total creatine pool size determined by the D3-creatine dilution method to lean body mass determined by independent methods. The tracer dose of D3-creatine (<1 mg/rat) was >99% bioavailable with 0.2–1.2% urinary spillage. Isotopic steady state was achieved within 24–48 h. Creatine pool size calculated from urinary D3-creatinine enrichment at 72 h significantly increased with muscle accrual in rat growth, significantly decreased with dexamethasone-induced skeletal muscle atrophy, was correlated with lean body mass ( r = 0.9590; P < 0.0001), and corresponded to predicted total muscle mass. Total-body creatine pool size and skeletal muscle mass can thus be accurately and precisely determined by an orally delivered dose of D3-creatine followed by the measurement of D3-creatinine enrichment in a single urine sample and is promising as a noninvasive tool for the clinical determination of skeletal muscle mass.

Starting from the micromolar 8-quinoline carboxamide high-throughput screening hit 1a, a systematic exploration of the structure-activity relationships (SAR) of the 4-, 6-, and 8-substituents of the quinoline ring resulted in the identification of approximately 10-100-fold more potent human CD38 inhibitors. Several of these molecules also exhibited pharmacokinetic parameters suitable for in vivo animal studies, including low clearances and decent oral bioavailability. Two of these CD38 inhibitors, 1ah and 1ai, were shown to elevate NAD tissue levels in liver and muscle in a diet-induced obese (DIO) C57BL/6 mouse model. These inhibitor tool compounds will enable further biological studies of the CD38 enzyme as well as the investigation of the therapeutic implications of NAD enhancement in disease models of abnormally low NAD.