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  • Mammals adapt to prolonged periods of food scarcity by relea

    2021-10-21

    Mammals adapt to prolonged periods of food scarcity by releasing FFAs from adipose tissue and transforming them into energy-rich ketone bodies that are used as fuel by brain, muscle, and other organs (Kersten, 2014, Grabacka et al., 2016). Ketogenesis occurs primarily in hepatocytes, but its rate is regulated by a combination of local and systemic factors. Systemic signals, such as the catabolic hormones glucagon and epinephrine, accelerate lipolysis and facilitate FFA transport into hepatocytes, where these lipids may serve as both precursors for ketone bodies and agonists for the master transcriptional regulator of ketogenesis, PPAR-α (Montagner et al., 2016, Dubois et al., 2017). Nevertheless, the fact that FFAs activate this nuclear receptor only at mid to high micromolar concentrations (Gottlicher et al., 1992, Berger and Moller, 2002), which are unlikely to occur in healthy YM201636 (Yamashita et al., 1997), challenges a simplistic interpretation of this model and suggests that additional ligands might be implicated in fasting-induced activation of PPAR-α in liver (Chakravarti, 2009, Kersten, 2014). Our results show that ketogenesis is substantially dampened, but not completely suppressed, by genetic or pharmacological manipulations that disrupt histamine-driven OEA biosynthesis. A plausible interpretation of this finding is that OEA acts in concert with FFAs (and/or, possibly, other endogenous ligands) (Chakravarti, 2009) to engage PPAR-α and promote ketogenesis (Figure 7). Histamine-releasing neurons housed in the tuberomamillary nucleus of the hypothalamus regulate circadian feeding and mediate, in part, the satiety response initiated by OEA mobilization in the small intestine (Provensi et al., 2014, DiPatrizio and Piomelli, 2015). In addition to these central anorexic effects, which depend on H1 receptor activation (Haas et al., 2008), histamine also contributes in important ways to the peripheral control of energy balance and lipid metabolism. Indeed, in mice, genetic H1 receptor deletion causes increased abdominal adiposity and glucose intolerance (Masaki et al., 2001b), while pharmacological H1 blockade aggravates HFD-induced hepatic steatosis (Raveendran et al., 2014). Similarly, in obese humans, chronic use of H1 antagonists, which are commonly prescribed to alleviate allergy symptoms, is associated with increased weight gain and insulin resistance (Ratliff et al., 2010). H1 blockade has been also implicated in the weight gain and dyslipidemia that often accompany the protracted use of atypical antipsychotic drugs (Nasrallah, 2008). The mechanism(s) underlying these dysmetabolic actions is unclear. However, our finding that the H1 antagonist fexofenadine disables histamine-dependent signaling and impairs ketogenesis points to a possible explanation, which warrants, of course, further investigation.
    STAR★Methods
    Acknowledgments We thank Dr. T. Feyerabend and Prof. H.R. Rodewald for Cpa3 mutant mice and critical reading of the manuscript; Drs. S. Galli, S. Pontis, N. Realini, F. Palese, and P. Blandina for advice and support; Drs. A. Basit and M.E. Blanco for LC/MS analyses; and A. Costa for help with sample collection.
    Introduction Among Chinese children, 3.1–9.8% suffer from asthma, allergic rhinitis, and/or eczema. Although most cases of allergic diseases are not life-threatening, their prevalence is increasing and they contribute to impair the activities of daily life such as work, sleep, social interactions, and study. In addition, allergic diseases impose an important socioeconomic burden on the patients. Various tests are available for the diagnosis of allergic diseases, including the provocation test, skin prick test (SPT), and multiple allergen simultaneous test. Each of YM201636 these tests has advantages and limitations, and the SPT is commonly used. During the SPT, histamine is used as a positive control to rule out false-negative results and as a comparator for the allergic reactions. Nevertheless, histamine skin reactions may be affected by drugs, disease history, method of testing, age, gender, testing season, examiner, and pricking device, resulting in wide variations of the histamine skin reactions among individuals.4, 5, 6, 7, 8 There is still a lack of understanding about differences among individuals regarding the skin reactivity to histamine.