Background The apelin system is a novel peptidic pathway widely expressed in the
heart and vasculature. In preclinical studies, apelin receptor agonism mediates
nitric oxide-dependent vasodilatation, reduces ventricular preload and afterload and
potently increases myocardial contractility. In preclinical models of heart failure,
expression of the apelin pathway is down regulated but the haemodynamic effects of
apelin receptor agonism are preserved. These changes in expression appear to be
paralleled in patients with chronic heart failure but the cardiovascular actions of
apelin in vivo in man are, to date, unknown. Detailed clinical investigation is
therefore required to establish the role of apelin in human cardiovascular physiology
and pathophysiology and to explore the therapeutic potential of apelin receptor
agonism in patients with heart failure.
Objectives Through a series of in vivo clinical studies: 1) to establish the direct
vascular actions of apelin in the peripheral venous, peripheral arterial and coronary
arterial circulations; 2) to determine the contribution of the endothelium-derived
vasodilators, nitric oxide and prostacyclin, to the vascular actions of apelin; 3) to
establish the effects of apelin on cardiac contractility and systemic haemodynamics;
4) to compare the direct vascular and systemic haemodynamic effects of the fulllength
mature apelin peptide, apelin-36, with a shorter, biologically active carboxyl
(C)-terminal fragment, (Pyr1)apelin-13); and 5) to establish whether the local
vascular and systemic haemodynamic effects of apelin are altered in patients with
chronic heart failure.
Methods The cardiovascular effects of apelin were assessed in 32 healthy
volunteers, 6 patients undergoing elective diagnostic coronary angiography,
18 patients with stable New York Heart Association (NYHA) class II-III chronic
heart failure and 18 age- and sex-matched healthy controls. Dorsal hand vein tone
was assessed by the Aellig hand vein technique during local intravenous
infusions (0.1-3 nmol/min) of apelin-36, (Pyr1)apelin-13, and sodium nitroprusside
(SNP; 0.6 nmol/min). Forearm blood flow was measured by venous occlusion
plethysmography during intrabrachial infusions of apelin-36 and (Pyr1)apelin-13
(0.01-30 nmol/min) and subsequently in the presence or absence of a ‘nitric oxide
clamp’ (nitric oxide synthase inhibitor, L-NG-monomethylarginine (L-NMMA;
8 μmol/min), co-infused with SNP (90-900 ng/min)), or a single oral dose of aspirin
(600 mg) or matched placebo. Coronary blood flow was evaluated by quantitative
coronary angiography (QCA) and Doppler flow wire, and left ventricular pressures
measured by pressure wire before and after intracoronary injection of apelin-36
(20 and 200 nM), 0.9% saline and glyceryl trinitrate (GTN) (100 μg). Blood
pressure, heart rate, cardiac output and peripheral vascular resistance were assessed
by sphygmomanometry and thoracic electrical bioimpedance (TEB) during systemic
intravenous infusion of apelin-36 and (Pyr1)apelin-13 (30-300 nmol/min). Forearm
blood flow and systemic haemodynamic responses to (Pyr1)apelin-13 in patients with
chronic heart failure were then compared with age- and sex-matched healthy
controls.
Results Although SNP caused venodilatation (P<0.0001), apelin-36 and
(Pyr1)apelin-13 had no effect on dorsal hand vein diameter (P=0.2). Both apelin
isoforms caused vasodilatation in forearm resistance vessels (P<0.0001) but the
offset was slower with apelin-36. (Pyr1)apelin-13-mediated vasodilatation was
attenuated by the nitric oxide clamp (P=0.004) but unaffected by aspirin (P=0.7).
Intracoronary bolus of apelin-36 increased coronary blood flow and the maximum
rate of rise in left ventricular pressure, and reduced peak and end-diastolic left
ventricular pressures (all P<0.05). Both (Pyr1)apelin-13 and apelin-36 increased
heart rate and cardiac output whilst reducing peripheral vascular resistance (P<0.01
for all) with no overall effect on blood pressure. Intrabrachial infusions of
(Pyr1)apelin-13, acetylcholine and SNP caused forearm vasodilatation in patients and
controls (P<0.0001 for all). Vasodilatation to acetylcholine (P=0.01) but not apelin
(P=0.3) or SNP (p=0.9) was attenuated in patients with heart failure. Systemic
infusions of (Pyr1)apelin-13 increased cardiac index and lowered mean arterial
pressure and peripheral vascular resistance index in patients and matched controls
(all P<0.01) but increased heart rate only in controls (P<0.01).
Conclusions Although having no apparent effect on venous tone, acute apelin
receptor agonism causes peripheral and coronary vasodilatation and increases cardiac
contractility and output. Local vascular and systemic haemodynamic responses to
apelin are preserved in patients with stable symptomatic chronic heart failure. The
apelin system merits further clinical investigation to determine its role in
cardiovascular homeostasis and represents a novel potential therapeutic target for
patients with heart failure.

Cardiovascular effects of apelin in vivo in man

Cardiovascular diseases are the leading cause of death worldwide Overweight and obesity are strongly associated with comorbidities such as hypertension and insulin resistance, which collectively contribute to the development of cardiovascular diseases and resultant morbidity and mortality Forty-two percent of adults in the United States are obese, and a total of 19 billion adults worldwide are overweight or obese These alarming numbers, which continue to climb, represent a major health and economic burden Adipose tissue is a highly dynamic organ that can be classified based on the cellular composition of different depots and their distinct anatomical localization Massive expansion and remodeling of adipose tissue during obesity differentially affects specific adipose tissue depots and significantly contributes to vascular dysfunction and cardiovascular diseases Visceral adipose tissue accumulation results in increased immune cell infiltration and secretion of vasoconstrictor mediators, whereas expansion of subcutaneous adipose tissue is less harmful Therefore, fat distribution more than overall body weight is a key determinant of the risk for cardiovascular diseases Thermogenic brown and beige adipose tissue, in contrast to white adipose tissue, is associated with beneficial effects on the vasculature The relationship between the type of adipose tissue and its influence on vascular function becomes particularly evident in the context of the heterogenous phenotype of perivascular adipose tissue that is strongly location dependent In this review, we address the abnormal remodeling of specific adipose tissue depots during obesity and how this critically contributes to the development of hypertension, endothelial dysfunction, and vascular stiffness We also discuss the local and systemic roles of adipose tissue derived secreted factors and increased systemic inflammation during obesity and highlight their detrimental impact on cardiovascular health

Obesity, Adipose Tissue and Vascular Dysfunction.

As described previously, the regulatory roles played by the autonomic nervous system on blood glucose homeostasis is well documented in comparison with those on fat and protein metabolism. It can be summarized as follows: It was shown that an increase in blood glucose concentration produced an increase in the activity of the pancreatic branch of the vagus nerve whereas it induced a decrease in the activity of the pancreatic branch of the splanchnic nerve and adrenal nerve. It was also shown that a decrease in blood glucose concentration activated the sympatho-adrenal system and suppressed vago-pancreatic system. It seems rational that these responses are involved in the maintenance of blood glucose level. Studies on the innervation of the liver led us to a conclusion that sympathetic innervation of the liver plays a role in eliciting a prompt hyperglycemic response through liberation of norepinephrine from the nerve terminals, and that the vagal innervation synergically worked with the humoral factor (insulin) for glycogen synthesis in the hyperglycemic condition. The glucose-sensitive afferents from the liver seem to initiate a reflex control of blood glucose level. The gustatory information on early insulin response (EIR), reported by Steffens (1976), is supported by the electrophysiological observations. Mei's reports (1981) also indicated the importance of information from the intestinal glucoreceptors in the reflex control of insulin secretion via the vagus, which has been proved electrophysiologically. The role of integrative function of the hypothalamus and brainstem through neuronal networks on neural control of blood glucose homeostasis is evident. On the neural control of fat metabolism, it is evident that the sympathetic outflows to the brown adipose tissue as well as white adipose tissue predominantly play important roles. However, there is still little information on the central mechanism played by the hypothalamus on the fat metabolism and the neural pathways from the hypothalamus to the sympathetic motoneurons innervating adipose tissues. The reports on the neural control of protein metabolism are very few. Only several studies were reported on the liver function in relation to the protein metabolism. Further extensive studies should be expected.

Nervous regulation of the metabolism

Obesity is a chronic metabolic disease caused by multiple factors and is considered to be a risk factor for type 2 diabetes, cardiovascular disease, hypertension, stroke and various cancers. Hesperidin, a flavanone glycoside, is a natural phenolic compound with a wide range of biological effects. Mounting evidence has demonstrated that hesperidin possesses inhibitory effect against obesity diseases. Our review discusses mechanisms of hesperidin in the treatment of obesity. Hesperidin regulates lipid metabolism and glucose metabolism by mediating AMPK and PPAR signaling pathways, directly regulates antioxidant index and anti-apoptosis, and indirectly mediates NF-κB signaling pathway to regulate inflammation to play a role in the treatment of obesity. In addition, hesperidin-enriched dietary supplements can significantly improve symptoms such as postprandial hyperglycemia and hyperlipidemia. Further clinical trials are also required for confirming lipid-lowering efficacy of this natural flavonoid and evaluating its safety profile.

/pdf/hesperidin-a-therapeutic-agent-for-obesity-4v120kar0b.pdf

Hesperidin: A Therapeutic Agent For Obesity

Obesity is a condition of rising prevalence worldwide, with important socioeconomic implications, being considered as a growing public health concern. Frequently, obesity brings other complications in addition to itself—like Type 2 Diabetes Mellitus (T2DM)—sharing origin, risk factors and pathophysiological mechanisms. In this context, some authors have decided to include both conditions as a unique entity known as “diabesity”. In fact, understanding diabesity as a single disease is possible to maximise the benefits from therapies received in these patients. Gut microbiota plays a key role in individual’s health, and their alterations, either in its composition or derived products are related to a wide range of metabolic disorders like T2DM and obesity. The present work aims to collect the different changes reported in gut microbiota in patients with T2DM associated with obesity and their possible role in the onset, development, and establishment of the disease. Moreover, current research lines to modulate gut microbiota and the potential clinical translation derived from the knowledge of this system will also be reviewed, which may provide support for a better clinical management of such a complex condition.

https://www.mdpi.com/2072-6643/12/9/2749/pdf

Type 2 Diabetes Mellitus Associated with Obesity (Diabesity). The Central Role of Gut Microbiota and Its Translational Applications

Obesity is increasingly prevalent and is associated with substantial cardiovascular risk. Adipose tissue distribution and morphology play a key role in determining the degree of adverse effects, and a key factor in the disease process appears to be the inflammatory cell population in adipose tissue. Healthy adipose tissue secretes a number of vasoactive adipokines and anti-inflammatory cytokines, and changes to this secretory profile will contribute to pathogenesis in obesity. In this review, we discuss the links between adipokine dysregulation and the development of hypertension and diabetes and explore the potential for manipulating adipose tissue morphology and its immune cell population to improve cardiovascular health in obesity.

/pdf/mechanistic-links-between-obesity-diabetes-and-blood-24pbz8jz9c.pdf

Ben J. Clark

Papers

Mechanistic Links Between Obesity, Diabetes, and Blood Pressure: Role of Perivascular Adipose Tissue.