The hormone GDF15 is secreted in response to cellular stressors. Metformin elevates circulating levels of GDF15, an action important for the drug's beneficial effects on body weight. Metformin can ...also inhibit mammalian respiratory complex I, leading to decreases in ATP:AMP ratio, activation of AMP Kinase (AMPK), and increased GDF15 production. We undertook studies using a range of mice with tissue-specific loss of Gdf15 (namely gut, liver and global deletion) to determine the relative contributions of two classical metformin target tissues, the gut and liver, to the elevation of GDF15 seen with metformin. In addition, we performed comparative studies with another pharmacological agent, the AMP kinase pan-activator, MK-8722. Deletion of Gdf15 from the intestinal epithelium significantly reduced the circulating GDF15 response to oral metformin, whereas deletion of Gdf15 from the liver had no effect. In contrast, deletion of Gdf15 from the liver, but not the gut, markedly reduced circulating GDF15 responses to MK-8722. Further, our data show that, while GDF15 restricts high-fat diet-induced weight gain, the intestinal production of GDF15 is not necessary for this effect. These findings add to the body of evidence implicating the intestinal epithelium in key aspects of the pharmacology of metformin action.
Metformin and GDF15: where are we now? Kincaid, John W R; Coll, Anthony P
Nature reviews. Endocrinology,
01/2023, Letnik:
19, Številka:
1
Journal Article
NAD metabolism in aging and cancer Kincaid, John WR; Berger, Nathan A
Experimental biology and medicine (Maywood, N.J.),
11/2020, Letnik:
245, Številka:
17
Journal Article
Recenzirano
Odprti dostop
NAD+ and its derivatives NADH, NADP+, and NADPH are essential cofactors in redox reactions and electron transport pathways. NAD serves also as substrate for an extensive series of regulatory enzymes ...including cyclic ADP-ribose hydrolases, mono(ADP-ribosyl)transferases, poly(ADP-ribose) polymerases, and sirtuin deacetylases which are O-acetyl-ADP-ribosyltransferases. As a result of the numerous and diverse enzymes that utilize NAD as well as depend on its synthesis and concentration, significant interest has developed in its role in a variety of physiologic and pathologic processes, and therapeutic initiatives have focused both on augmenting its levels as well as inhibiting some of its pathways. In this article, we examine the biosynthesis of NAD, metabolic processes in which it is involved, and its role in aging, cancer, and other age-associated comorbidities including neurodegenerative, cardiovascular, and metabolic disorders. Therapeutic interventions to augment and/or inhibit these processes are also discussed.
Impact statement
NAD is a central metabolite connecting energy balance and organismal growth with genomic integrity and function. It is involved in the development of malignancy and has a regulatory role in the aging process. These processes are mediated by a diverse series of enzymes whose common focus is either NAD’s biosynthesis or its utilization as a redox cofactor or enzyme substrate. These enzymes include dehydrogenases, cyclic ADP-ribose hydrolases, mono(ADP-ribosyl)transferases, poly(ADP-ribose) polymerases, and sirtuin deacetylases. This article describes the manifold pathways that comprise NAD metabolism and promotes an increased awareness of how perturbations in these systems may be important in disease prevention and/or progression.
Abstract
Context
The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In ...population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown.
Objective
This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).
Methods
We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort.
Results
MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 2.2%; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 0.6%; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07).
Conclusion
We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.
Objective
Obesity has emerged as a prominent risk factor for multiple serious disease states, including a variety of cancers, and is increasingly recognized as a primary contributor to preventable ...cancer risk. However, few studies of leukemia have been conducted in animal models of obesity. This study sought to characterize the impact of obesity, diet, and sex in a murine model of acute promyelocytic leukemia (APL).
Methods
Male and female C57BL/6J.mCG+/PR mice, genetically predisposed to sporadic APL development, and C57BL/6J (wild type) mice were placed on either a high‐fat diet (HFD) or a low‐fat diet (LFD) for up to 500 days.
Results
Relative to LFD‐fed mice, HFD‐fed animals displayed increased disease penetrance and shortened disease latency as indicated by accelerated disease onset. In addition, a diet‐responsive sex difference in APL penetrance and incidence was identified, with LFD‐fed male animals displaying increased penetrance and shortened latency relative to female counterparts. In contrast, both HFD‐fed male and female mice displayed 100% disease penetrance and insignificant differences in disease latency, indicating that the sexual dimorphism was reduced through HFD feeding.
Conclusions
Obesity and obesogenic diet promote the development of APL in vivo, reducing sexual dimorphisms in disease latency and penetrance.
Background. Microembolization during cardiopulmonary bypass (CPB) can be detected in the brain as lipid deposits that create small capillary and arteriolar dilations (SCADs) with ischemic injury and ...neuronal dysfunction. SCAD density is increased with the use of cardiotomy suction to scavenge shed blood. Our purpose was to determine whether various methods of processing shed blood during CPB decrease cerebral lipid microembolic burden.
Methods. After hypothermic CPB (70 minutes), brain tissue from two groups of mongrel dogs (28 to 35 kg) was examined for the presence of SCADs. In the arterial filter (AF) group (n = 12), shed blood was collected in a cardiotomy suction reservoir and reinfused through the arterial circuit. Three different arterial line filters (Pall LeukoGuard, Pall StatPrime, Bentley Duraflo) were used alone and in various combinations. In the cell saver (CS) group (n = 12), shed blood was collected in a cell saver with intermittent preocessing (Medtronic autoLog model) or a continuous-action cell saver (Fresenius Continuous Auto Transfusion System) and reinfused with and without leukocyte filtration through the CPB circuit.
Results. Mean SCAD density (SCAD/cm
2) in the CS group was less than the AF group (11 ± 3 vs 24 ± 5,
p = 0.02). There were no significant differences in SCAD density with leukocyte filtration or with the various arterial line filters. Mean SCAD density for the continuous-action cell saver was 8 ± 2 versus 13 ± 5 for the intermittent-action device.
Conclusions. Use of a cell saver to scavenge shed blood during CPB decreases cerebral lipid microembolization.
Six healthy adult male mongrel dogs underwent cranial cruciate ligament transection in the left stifle. Survey radiography of both stifles and low‐field (0.064 T) MRI of the left stifle were ...performed preoperatively and at 2, 6, and 12 weeks postoperatively. Focal changes in signal intensity were seen with MRI in the subchondral bone of the medial tibial condyle at 2 and 6 weeks postoperatively. At 12 weeks postoperative, a cyst‐like lesion was detected using MRI in the subchondral bone of the medial tibial condyle in 4 of 6 dogs and a less defined lesion at this site in the remaining 2 dogs. The cyst‐like lesion was spherical in shape and showed typical characteristics of fluid with low signal intensity on T1‐weighted images, high signal intensity on T2‐weighted images and high signal intensity on inversion recovery images. The lesion was seen in the subchondral bone of the caudal medial and/or middle region of the tibial plateau slightly cranial to the insertion of the caudal cruciate ligament. No subchondral cysts were seen in the tibia on radiographs. Histopathologically, the tibia was characterized by a loose myxomatous phase of early subchondral cyst formation.
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