The worldwide epidemic of obesity has brought considerable attention to research aimed at understanding the biology of adipocytes (fat cells) and the events occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and that this contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders. Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have pro-inflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this Review, we focus on the role of adipokines in inflammatory responses and discuss their potential as regulators of metabolic function.

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Adipokines in inflammation and metabolic disease

Obesity-related disorders are associated with the development of ischemic heart disease. Adiponectin is a circulating adipose-derived cytokine that is downregulated in obese individuals and after myocardial infarction. Here, we examine the role of adiponectin in myocardial remodeling in response to acute injury. Ischemia-reperfusion in adiponectin-deficient (APN-KO) mice resulted in increased myocardial infarct size, myocardial apoptosis and tumor necrosis factor (TNF)-α expression compared with wild-type mice. Administration of adiponectin diminished infarct size, apoptosis and TNF-α production in both APN-KO and wild-type mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF-α production. Dominant negative AMP-activated protein kinase (AMPK) reversed the inhibitory effects of adiponectin on apoptosis but had no effect on the suppressive effect of adiponectin on TNF-α production. Adiponectin induced cyclooxygenase (COX)-2–dependent synthesis of prostaglandin E2 in cardiac cells, and COX-2 inhibition reversed the inhibitory effects of adiponectin on TNF-α production and infarct size. These data suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2–dependent mechanisms.

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Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2—dependent mechanisms

Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome.

Obesity is strongly associated with hypertension and cardiovascular disease. Several central and peripheral abnormalities that can explain the development or maintenance of high arterial pressure in obesity have been identified. These include activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Obesity is also associated with endothelial dysfunction and renal functional abnormalities that may play a role in the development of hypertension. The continuing discovery of mechanisms regulating appetite and metabolism is likely to lead to new therapies for obesity-induced hypertension. Better understanding of leptin signaling in the hypothalamus and the mechanisms of leptin resistance should facilitate therapeutic approaches to reverse the phenomenon of selective leptin resistance. Other hunger and satiety signals such as ghrelin and peptide YY are potentially attractive therapeutic strategies for treatment of obesity and its complications. These recent discoveries should lead to novel strategies for treatment of obesity and hypertension.

Obesity-Associated Hypertension. New Insights Into Mechanisms

Adiponectin is the most abundant peptide secreted by adipocytes, whose reduction plays a central role in obesity-related diseases, including insulin resistance/type 2 diabetes and cardiovascular disease. In addition to adipocytes, other cell types, such as skeletal and cardiac myocytes and endothelial cells, can also produce this adipocytokine. Adiponectin effects are mediated by adiponectin receptors, which occur as two isoforms (AdipoR1 and AdipoR2). Adiponectin has direct actions in liver, skeletal muscle, and the vasculature.Adiponectin exists in the circulation as varying molecular weight forms, produced by multimerization. Several endoplasmic reticulum ER-associated proteins, including ER oxidoreductase 1-α (Ero1-α), ER resident protein 44 (ERp44), disulfide-bond A oxidoreductase-like protein (DsbA-L), and glucose-regulated protein 94 (GPR94), have recently been found to be involved in the assembly and secretion of higher-order adiponectin complexes. Recent data indicate that the high-molecular weight (HMW) complexes have the predominant action in metabolic tissues. Studies have shown that adiponectin administration in humans and rodents has insulin-sensitizing, anti-atherogenic, and anti-inflammatory effects, and, in certain settings, also decreases body weight. Therefore, adiponectin replacement therapy in humans may suggest potential versatile therapeutic targets in the treatment of obesity, insulin resistance/type 2 diabetes, and atherosclerosis. The current knowledge on regulation and function of adiponectin in obesity, insulin resistance, and cardiovascular disease is summarized in this review.

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Adiponectin, a Therapeutic Target for Obesity, Diabetes, and Endothelial Dysfunction

Adiponectin is one of the key molecules in the metabolic syndrome, and its concentration is decreased in obesity, type-2 diabetes, and coronary artery disease. Genetic investigation has revealed th...

Hypoadiponectinemia Is an Independent Risk Factor for Hypertension

P-121: UCSNP-43 G/A polymorphism of calpain-10 gene is associated with hypertension and dyslipidemia in Japanese population

Effects of Rikkunshi-To, a Japanese kampo medicine, on donepezil-induced gastrointestinal side effects in mice.

Aim: We investigated whether antihypertensive drugs and diuretics were associated with adverse drug reactions in the older inpatients. Methods: We retrospectively investigated factors related to adverse drug reactions(ADRs) in inpatients aged 65 and over in the geriatrics and hypertension ward of Osaka University Hospital in Japan. We identified drug information and ADRs from the medical records of 1031 inpatients during the 7 years from September 2014 to August 2021. Results: There were 94 ADRs in 81 patients(7.9%) of the total of 1031 patients (female 54.0%, mean age 78.1 ± 6.7 years), there happened the most in 24 cases is with antihypertensive drugs, and the second most in 15 casess is with diuretics. Of the 24 cases of ADRs thought to be caused by antihypertensive drugs, 20 cases of ADR occurred with antihypertensive drugs taken before admission. The details of ADRs by antihypertensive drugs were hypotention / orthostatic hypotension in 16 cases, bradycardia in 7 cases, and edema in 1 case. Of the 15 cases of ADRs thought to be caused by diuretics, 10 cases of ADRs occurred with diuretics that had been taken before admission. The details of ADRs by diuretics were electrolyte abnormalities in 8 cases, hypotension / orthostatic hypotension in 6 cases, and renal dysfunction in 1 case. Of the 24 cases in which antihypertensive drugs were suspected to be ADRs, the most common disease were heart failure in 7 cases, followed by hypertension in 4 cases. Of the 15 cases in which diuretics were suspected to be ADRs, the most common diseases were heart failure (3 cases) and diabetes (3 cases). However, the results of multivariate analysis showed no significant association between the disease that triggered admission and the occurrence of ADRs. Conclusions: The subjects of this study included many patients with hypertension and heart failure, and since they used many antihypertensive drugs and diuretics, there were many ADRs caused by them. The same situation seems to be naturally accepted in medical care for the older people. It is important to be aware that antihypertensive drugs and diuretics, being the most common in medical care for the older people, may cause ADRs.

Ps-c31-11: the relation between antihypertensive drugs and diuretics and adverse drug reactions in the older inpatients

Donepezil is used for treatment of Alzheimer's disease, but it is associated with increased risk for gastrointestinal (GI) symptoms, such as anorexia, nausea, and vomiting. Their insufficient control affects the ability to continue the donepezil therapy. Rikkunshi-To (RKT), a traditional herbal Japanese medicine, has been prescribed for patients with various GI symptoms because it improves the GI function via the potentiation of ghrelin signaling pathway. In this study, we investigated the effects of RKT on the prevention of donepezil-induced anorexia, nausea, and vomiting in mice and the involvement of ghrelin in its therapeutic effect. We have reported that donepezil (5mg/kg, i.p.) induced anorexia and pica, kaolin ingestion behavior, could be used to evaluate nausea and vomiting in mice fed the normal diet. Mice fed the diet supplemented with RKT (1%) did not show donepezil-induced anorexia and pica, and this therapeutic effect was antagonized by pretreatment with the ghrelin receptor antagonist. Donepezil significantly suppressed the intestinal motility in mice fed the normal diet; however, RKT recovered the motility delay. Furthermore, the ghrelin receptor antagonist reduced the effect of RKT to improve the intestinal motility. These findings suggest that RKT is a candidate for the treatment of donepezil induced anorexia, nausea, and vomiting in human patients, and that the enhancement of ghrelin signaling is involved in its therapeutic effect. Oral Sessions

Kouichi Yamamoto

Papers

Hypoadiponectinemia Is an Independent Risk Factor for Hypertension

P-121: UCSNP-43 G/A polymorphism of calpain-10 gene is associated with hypertension and dyslipidemia in Japanese population

Effects of Rikkunshi-To, a Japanese kampo medicine, on donepezil-induced gastrointestinal side effects in mice.

Ps-c31-11: the relation between antihypertensive drugs and diuretics and adverse drug reactions in the older inpatients

Effects of Rikkunshi-To on the donepezil-induced gastrointestinal symptoms in mice