Cleasby, M E

Diabetes

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Mark E. Cleasby

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ANP-ing Up Diabetes: Impaired Natriuretic Peptide Action in Muscle Forms a Mechanistic Link Between Obesity and Diabetes

RVC Research Online

  RVC OPEN ACCESS REPOSITORY – COPYRIGHT NOTICE  "This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at : http://diabetes.diabetesjournals.org/content/64/12/3978.    The full details of the published version of the article are as follows: TITLE: ANP-ing Up Diabetes: Impaired Natriuretic Peptide Action in Muscle Forms a Mechanistic Link Between Obesity and Diabetes AUTHORS: Mark E. Cleasby JOURNAL TITLE: Diabetes PUBLISHER:  American Diabetes Association PUBLICATION DATE: December 2015 DOI: 10.2337/dbi15-0017 ANP-ing up diabetes: impaired natriuretic peptide action 1 in muscle forms a mechanistic link between obesity and 2 diabetes 3  4 Mark E Cleasby 5  6 Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, 7 United Kingdom. 8  9 Corresponding author: Dr. Mark E Cleasby, mcleasby@rvc.ac.uk. 10  11 Word Count: 1,025 12  13 Number of Figures: 1 14   15 A growing body of work concerns the role of natriuretic peptides (NPs) in metabolism and insulin 16 sensitivity, the latest addition to which is published in this issue of Diabetes (1). Three principal 17 structurally related NPs exist in mammals: atrial natriuretic peptide (ANP), produced primarily by the 18 cardiac atria, brain/B-type natriuretic peptide (BNP), secreted by the ventricle and brain, and C-type 19 natriuretic peptide (CNP), originating from vascular endothelium, central nervous system and kidney. 20 They were originally shown to possess potent natriuretic, diuretic and vasodilatory activity, thus 21 playing a significant role in the prevention of circulatory volume overload and hypertension. These 22 peptides utilise plasma membrane-situated natriuretic peptide receptors (NPR) A and B, with the A 23 receptor showing preference for ANP and BNP and the B receptor being specific for CNP, while a 24 distinct C receptor is responsible for peptide clearance in tissues. Binding of peptides to NPRA leads 25 to activation of intracellular cGMP-dependent signalling cascades involving cGMP-dependent protein 26 kinases, phosphodiesterases and ion channels that mediate the physiological effects of NPs (reviewed 27 in (2)). 28 Recently, parallel metabolic actions of NPs have also been demonstrated in adipose tissue, with 29 selective effects in the visceral adipose depot, expansion of which is most associated with insulin 30 resistance. ANP-stimulated cGMP-mediated phosphorylation of hormone-sensitive lipase results in 31 lipolysis in primates/humans that is independent of beta-adrenergic stimulation (3-5), thereby 32 inhibiting visceral adipocyte hypertrophy (6). In addition, ANP treatment causes reduced adipose 33 secretion of pro-inflammatory cytokines and increased secretion of the insulin sensitising adipokine 34 adiponectin (7), while BNP infusion induces “browning” of white adipose tissue, and thus increased 35 energy expenditure (8), both of which effects would be likely to ameliorate insulin resistance (IR). 36 Furthermore, cross-sectional studies of large cohorts showed associations between reduced plasma 37 NPs and both obesity and IR (9-11), while low plasma ANP also predicts the subsequent development 38 of type 2 diabetes (T2D) (12). The combination of reduced cardiac NP secretion and/or increased 39 clearance in obesity has been termed the “natriuretic handicap” (13). 40 However, not only is visceral adiposity an independent determinant of plasma BNP in healthy 41 individuals, but so is muscle mass (14). In addition, NPRA is upregulated in muscle from exercise-42 trained individuals (15), implying that muscle may also functionally adapt in response to NPs released 43 from the exercising heart. The metabolic effects of NPs in muscle are starting to be elucidated and 44 could be of importance for diabetes, given that this tissue is responsible for the majority of insulin-45 stimulated glucose disposal. Mice with genetically-induced increases in plasma BNP or cGMP-46 dependent protein kinase activity both demonstrate reduced fat depot size after high fat diet (HFD) 47 feeding, accompanied by reduced ectopic lipid deposition in liver and muscle, due to increased 48 mitochondrial content and fat oxidation (16). Moreover, NP-induced increases mitochondrial fat 49 oxidation and/or uncoupling have been shown in cultured human muscle cells (15), while BNP 50 infusion can also protect against mitochondrial dysfunction and oxidative stress in muscle (17). 51 However, to date the mechanisms whereby obesity-induced impairment in the NP axis might lead to 52 the development of T2D have not been elucidated. 53 In this issue of Diabetes, Coué et al describe a series of studies in which they investigate whether 54 altered NP action in muscle might mediate  the natriuretic handicap and link obesity with diabetes (1). 55 Initially, they analysed protein expression of each in muscle biopsies from human volunteers with 56 varying degrees of body fat, obesity, impaired glucose tolerance (IGT) or T2D. Muscle NPRA protein 57 levels were correlated directly with insulin sensitivity and inversely with the degree of adiposity in 58 healthy volunteers, were reduced in obese subjects, but increased in response to diet-induced weight 59 loss. Conversely, NPRC was increased in obese individuals with IGT or T2D, implying overall that 60 NP action is likely to be impaired in muscle of obese or insulin resistant people. The authors then 61 investigated the physiological significance of these changes by studying HFD-fed and leptin receptor-62 deficient obese and diabetic db/db mice, which demonstrated consistent reductions in muscle NPRA, 63 up-regulation of NPRC in the latter model, and also impaired phosphorylation of p38 mitogen-64 activated protein kinase, a key downstream signalling intermediate. Acute infusion of BNP did not 65 affect glucose homeostasis, consistent with a lack of effect of acute NP treatment of primary human 66 muscle cells on glucose uptake. However, rescue of the natriuretic handicap by administration of BNP 67 to HFD-fed or db/db mice for four weeks resulted in improved glucose tolerance and insulin 68 responsiveness, without altering plasma insulin levels. These effects were accompanied by reduced 69 accumulation of the toxic lipid intermediates ceramide and diacylglycerol, improved insulin signalling 70 and mitochondrial fat oxidation in muscle. Interestingly, however, comparable effects were not 71 observed in either liver or adipose tissue. Following this up in cultured human myotubes, the authors 72 showed similar effects to those seen in mice. Whereas there were no acute effects of BNP on lipid 73 metabolism, three days of treatment led to reduced accumulation of lipids, including ceramide, and 74 increased fatty acid oxidation. Thus, in summary, the authors present evidence that NPs have a role in 75 maintaining muscle insulin sensitivity through limiting obesity-related local accumulation of lipotoxic 76 intermediates, and that this mechanism is impaired in T2D. Further work must identify the key 77 components of the signalling pathways involved in this mechanism. 78 Other recently published work suggests that the NP axis could be involved in mediating the effects of 79 obesity therapies, as improved NP sensitivity was demonstrated alongside adipose tissue browning as 80 part of the beneficial effect of bariatric surgery in a rodent model (18), while increased ANP release 81 and decreased clearance was involved in the effects of exercise in human subjects (19). This new 82 study (1) further implies that overcoming the natriuretic handicap in muscle could be a viable 83 approach for the treatment of T2D. Given that heart disease/hypertension and T2D are frequent 84 lifestyle-related co-morbidities and infusion of NPs can be used to treat the former, targeting of NPRs 85 may have promise as a future therapeutic approach for a significant sub-set of patients. However, NP 86 infusions represent an impractical means of treating diabetes chronically and it remains to be seen 87 whether drugs targeting NPRs or downstream signalling pathways will be developed and prove to be 88 effective in breaking the link between obesity and T2D. 89  90   91 Figure legend 92 Summary of natriuretic peptide action in skeletal muscle in healthy (A) and obese/diabetic (B) 93 individuals 94  95 Natriuretic peptides (NPs) circulate in reduced concentrations in obese/diabetic individuals than in 96 healthy individuals. Furthermore, expression of natriuretic peptide receptor A (NPRA), which binds 97 NPs and activates intracellular signaling events, is reduced, while expression of NPRC, which clears 98 NPs in tissues, is increased in obesity and type 2 diabetes. In healthy individuals, generation of cyclic 99 guanosine monophosphate (cGMP) from guanosine triphosphate (GTP) by the guanylyl cyclase 100 activity of NPRA activates a signaling pathway resulting in phosphorylation (P) and activation of p38 101 mitogen-activated protein kinase (p38 MAPK) and increased transcription of peroxisome proliferator-102 activated receptor coactivator 1α (PGC1α). This is associated with mitochondrial biogenesis and 103 oxidation of lipids, including the lipotoxic diacylglycerols (DAGs) and ceramides. 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ANP-ing Up Diabetes: Impaired Natriuretic Peptide Action in Muscle Forms a Mechanistic Link Between Obesity and Diabetes

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