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Melanocortin-4 receptor-expressing neurons in the paraventricular nucleus of the hypothalamus (PVH MC4R ) integrate hunger-promoting and hunger-suppressing signals to regulate satiety. Food consumption-evoked responses in PVH MC4R neurons increase gradually during meal consumption to promote satiety, and disrupting this process drives massive obesity. These critical satiety neurons are strongly affected by a high-fat diet, yet the impact on their functional properties remains unknown. We used fiber photometry to track PVH MC4R neurons’ responses to the consumption of drops of milkshake in animals fed a chow diet or a high-fat diet (HFD), both after obesity was established and after its reversal. PVH MC4R neurons in HFD-fed animals showed greater consumption-evoked responses than chow-fed animals at the early stages of meal consumption, and these responses did not increase further during the meal. HFD-fed animals also showed reduced licking vigor and motivation to consume milkshake. Switching HFD-fed obese animals to a normal chow diet (NCD) re-engaged the motivation to consume milkshake, partially restored early-meal neural responses to a lower level, but did not restore the increase in consumption-evoked response magnitude across the meal. These findings highlight functional alterations in hypothalamic satiety-promoting neurons in obesity and provide insight into the pathological neural consequences of an obesogenic environment.

Amyloid deposits in pancreatic islets, mainly formed by human islet amyloid polypeptide (hIAPP) aggregation, have been associated with loss of β-cell mass and function, and are a pathological hallmark of type 2 diabetes (T2D). Treatment with chaperones has been associated with a decrease in endoplasmic reticulum stress leading to improved glucose metabolism. The aim of this work was to investigate whether the chemical chaperone 4-phenylbutyrate (PBA) prevents glucose metabolism abnormalities and amyloid deposition in obese agouti viable yellow (A vy ) mice that overexpress hIAPP in β cells (A vy hIAPP mice), which exhibit overt diabetes. Oral PBA treatment started at 8 weeks of age, when A vy hIAPP mice already presented fasting hyperglycemia, glucose intolerance, and impaired insulin secretion. PBA treatment strongly reduced the severe hyperglycemia observed in obese A vy hIAPP mice in fasting and fed conditions throughout the study. This effect was paralleled by a decrease in hyperinsulinemia. Importantly, PBA treatment reduced the prevalence and the severity of islet amyloid deposition in A vy hIAPP mice. Collectively, these results show that PBA treatment elicits a marked reduction of hyperglycemia and reduces amyloid deposits in obese and diabetic mice, highlighting the potential of chaperones for T2D treatment.

The diabetic heart is characterised by functional, morphological and metabolic alterations predisposing it to contractile failure. Chronic sympathetic activation is a feature of the pathogenesis of heart failure, however the type 1 diabetic heart shows desensitisation to β-adrenergic stimulation. Here, we sought to understand the impact of repeated isoprenaline-mediated β-stimulation upon cardiac mitochondrial respiratory capacity and substrate metabolism in the 90% pancreatectomy (Px) rat model of type 1 diabetes. We hypothesised these hearts would be relatively protected against the metabolic impact of stress-induced cardiomyopathy. We found that individually both Px and isoprenaline suppressed cardiac mitochondrial respiration, but that this was preserved in Px rats receiving isoprenaline. Px and isoprenaline had contrasting effects on cardiac substrate metabolism, with increased reliance upon cardiac fatty acid oxidation capacity and altered ketone metabolism in the hearts of Px rats, but enhanced capacity for glucose uptake and metabolism in isoprenaline-treated rats. Moreover, Px rats were protected against isoprenaline-induced mortality, whilst isoprenaline elevated cGMP and protected myocardial energetic status in Px rat hearts. Our work suggests that adrenergic stimulation may be protective in the type 1 diabetic heart, and underlines the importance of studying pathological features in combination when modeling complex disease in rodents.

Dietary restriction (DR) decreases body weight, improves health, and extends lifespan. DR can be achieved by controlling how much and/or when food is provided, as well as by adjusting nutritional composition. Because these factors are often combined during DR, it is unclear which are necessary for beneficial effects. Several drugs have been utilized that target nutrient-sensing gene pathways, many of which change expression throughout the day, suggesting that the timing of drug administration is critical. Here, we discuss how dietary and pharmacological interventions promote a healthy lifespan by influencing energy intake and circadian rhythms. Circadian clocks link physiologic processes to environmental conditions and a mismatch between internal and external rhythms has negative effects on organismal health. In this review, the authors discuss the interactions between circadian clocks and dietary interventions targeted to promote healthy aging.

Early stages of the novel coronavirus disease (COVID-19) are associated with silent hypoxia and poor oxygenation despite relatively minor parenchymal involvement. Although speculated that such paradoxical findings may be explained by impaired hypoxic pulmonary vasoconstriction in infected lung regions, no studies have determined whether such extreme degrees of perfusion redistribution are physiologically plausible, and increasing attention is directed towards thrombotic microembolism as the underlying cause of hypoxemia. Herein, a mathematical model demonstrates that the large amount of pulmonary venous admixture observed in patients with early COVID-19 can be reasonably explained by a combination of pulmonary embolism, ventilation-perfusion mismatching in the noninjured lung, and normal perfusion of the relatively small fraction of injured lung. Although underlying perfusion heterogeneity exacerbates existing shunt and ventilation-perfusion mismatch in the model, the reported hypoxemia severity in early COVID-19 patients is not replicated without either extensive perfusion defects, severe ventilation-perfusion mismatch, or hyperperfusion of nonoxygenated regions. Early stages of the novel coronavirus disease (COVID-19) have been associated with silent hypoxia and poor oxygenation despite relatively small fractions of afflicted lung. Here, the authors present a mathematical model which reproduces the vascular pulmonary mechanisms observed in patients with early COVID-19.

Although classically appreciated for their role as the powerhouse of the cell, the metabolic functions of mitochondria reach far beyond bioenergetics. In this Review, we discuss how mitochondria catabolize nutrients for energy, generate biosynthetic precursors for macromolecules, compartmentalize metabolites for the maintenance of redox homeostasis and function as hubs for metabolic waste management. We address the importance of these roles in both normal physiology and in disease.

Brown and beige adipose tissue are emerging as distinct endocrine organs. These tissues are functionally associated with skeletal muscle, adipose tissue metabolism and systemic energy expenditure, suggesting an interorgan signaling network. Using metabolomics, we identify 3-methyl-2-oxovaleric acid, 5-oxoproline, and β-hydroxyisobutyric acid as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters. 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid induce a brown adipocyte-specific phenotype in white adipocytes and mitochondrial oxidative energy metabolism in skeletal myocytes both in vitro and in vivo. 3-methyl-2-oxovaleric acid and 5-oxoproline signal through cAMP-PKA-p38 MAPK and β-hydroxyisobutyric acid via mTOR. In humans, plasma and adipose tissue 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid concentrations correlate with markers of adipose browning and inversely associate with body mass index. These metabolites reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in mouse models of obesity and diabetes. Our findings identify beige adipose-brown adipose-muscle physiological metabokine crosstalk. Beige and brown fat may influence systemic metabolism through secreted signals. Here the authors identify a panel of metabolites secreted from beige and brown fat cells, which signal to influence fat tissue and skeletal muscle metabolism and have anti-obesity effects in mouse models of obesity and diabetes.

Hyperplastic expansion of white adipose tissue (WAT) relies in part on the proliferation of adipocyte precursor cells residing in the stromal vascular cell fraction (SVF) of WAT. This study reveals a circadian clock- and feeding-induced diurnal pattern of cell proliferation in the SVF of visceral and subcutaneous WAT in vivo, with higher proliferation of visceral adipocyte progenitor cells subsequent to feeding in lean mice. Fasting or loss of rhythmic feeding eliminates this diurnal proliferation, while high fat feeding or genetic disruption of the molecular circadian clock modifies the temporal expression of proliferation genes and impinges on diurnal SVF proliferation in eWAT. Surprisingly, high fat diet reversal, sufficient to reverse elevated SVF proliferation in eWAT, was insufficient in restoring diurnal patterns of SVF proliferation, suggesting that high fat diet induces a sustained disruption of the adipose circadian clock. In conclusion, the circadian clock and feeding simultaneously impart dynamic, regulatory control of adipocyte progenitor proliferation, which may be a critical determinant of adipose tissue expansion and health over time. During the expansion of adipose tissue adipocyte progenitor cells proliferate and undergo adipogenesis. Here, the authors show that adipocyte progenitor cell proliferation in visceral adipose tissue has a diurnal pattern, which is dependent on both energy intake and the circadian clock.

Supraphysiological doses of anabolic–androgenic steroids (AAS) is popular among recreational weightlifters and bodybuilders due to the performance-enhancing properties but is also associated with adverse cardiovascular effects. The knowledge about how AAS affect the vasculature is limited, although results from previous studies suggest alterations in vasoreactivity and morphology. In the present study we investigate the association between long-term use of AAS and vascular function. Hundred and twenty-three males were included in the study, 56 of them current AAS users and 67 weightlifting controls. Vascular function was evaluated by carotid artery reactivity and flow-mediated dilation. AAS users had significantly reduced carotid artery reactivity ( p  < 0.001) and flow-mediated dilation ( p  < 0.001) compared to weightlifting controls. Results from the present study indicate that long-term use of AAS affect the cardiovascular system negatively, measured as reduced carotid artery reactivity and flow-mediated dilation. These findings could partly explain sudden cardiovascular events among young long-term users of AAS.

Equol is an isoflavone (ISF)-derived metabolite by the gut microbiome in certain individuals termed equol-producers (EP). Equol might be the critical anti-atherogenic component of ISFs. In a population-based study of 979 Japanese men aged 40–79 without cardiovascular (CVD) or chronic kidney disease, we measured the urinary levels of equol and ISFs. Aortic calcification (AC) in the entire aorta was assessed by electron-beam or multi-detector-row computed tomography. Subjects with log10 (urinary equol to daidzein concentration) > − 1.5 were classified as EP. EP was further classified as person with low- and high-equol. We analyzed the association between equol-producing status and AC presence, defined as AC score > 0, by the logistic regressions. We found that EP (50% of the sample) had significantly lower odds of AC presence (odds ratio (OR): 0.62, 95% confidence interval (CI): 0.39, 0.98) compared to non-EP. This association was independent of CVD risk factors. For the dose–response association, compared to non-EP, subjects with low and high levels of equol had ORs of 0.51 (95% CI 0.30, 0.84) and 0.67 (95% CI 0.39, 1.14) after adjusting for major CVD risk factors ( p for trend = 0.06). ISFs concentrations were not significantly associated with AC presence (OR: 1.18, 95% CI: 0.82, 1.69). In conclusion, EP had a significantly lower burden of AC than non-EP, while ISFs were not associated with AC presence in Japanese men aged 40–79 years.