Central angiotensin II has catabolic action at white and brown adipose tissue

Abstract

Considerable evidence implicates the renin-angiotensin system (RAS) in the regulation of energy balance. To evaluate the role of the RAS in the central nervous system regulation of energy balance, we used osmotic minipumps to chronically administer angiotensin II (Ang II; icv; 0.7 ng/min for 24 days) to adult male Long-Evans rats, resulting in reduced food intake, body weight gain, and adiposity. The decrease in body weight and adiposity occurred relative to both ad libitum-and pair-fed controls, implying that reduced food intake in and of itself does not underlie all of these effects. Consistent with this, rats administered Ang II had increased whole body heat production and oxygen consumption. Additionally, chronic icv Ang II increased uncoupling protein-1 and ␤ 3-adrenergic receptor expression in brown adipose tissue and ␤3-adrenergic receptor expression in white adipose tissue, which is suggestive of enhanced sympathetic activation and thermogenesis. Chronic icv Ang II also increased hypothalamic agouti-related peptide and decreased hypothalamic proopiomelanocortin expression, consistent with a state of energy deficit. Moreover, chronic icv Ang II increased the anorectic corticotrophin-and thyroid-releasing hormones within the hypothalamus. These results suggest that Ang II acts in the brain to promote negative energy balance and that contributing mechanisms include an alteration in the hypothalamic circuits regulating energy balance, a decrease in food intake, an increase in energy expenditure, and an increase in sympathetic activation of brown and white adipose tissue. food intake; obesity; renin-angiotensin system MILLIONS OF PEOPLE SUFFER FROM OBESITY and the concomitant susceptibility to cardiovascular disease and type 2 diabetes, and emerging evidence has implicated the renin-angiotensin system (RAS) as contributing to these disorders; one consequence is that the RAS has emerged as a novel target for the treatment of these comorbidities (5,6,30,68,70,83). The RAS is best known as an endocrine system important in the regulation of cardiovascular function and hydromineral balance; however, recent evidence suggests that RAS also plays a substantial role in the regulation of energy and glucose homeostasis (5,6,30,68,70,83). Most physiological actions of the RAS are exerted by angiotensin II (Ang II), a peptide that is synthesized from angiotensinogen (AGT) via a series of proteolytic cleavage events. Drugs that reduce Ang II synthesis [angiotensinconverting enzyme (ACE) inhibitors] or action [angiotensin type 1 receptor blockers (ARBs)] have been used to treat hypertension for decades, and more recently, clinical and preclinical studies have explored the utility of these pharmacological agents to promote insulin sensitivity (1, 57). Interestingly, we and others have identified a potential novel utility of these pharmacological agents as therapeutics for obesity using animal models (4,16,21,76,84,85).Although interference with systemic RAS activity consistently decreases body weight and fat in rodent studie...

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

“…Augments whole-body heat production and oxygen consumption, and reduces body adipose mass through increased sympathetic activation via increased b 3 -adrenergic receptor expression in brown and white adipose tissue (de Kloet et al, 2011). Induces a profound reduction in both subcutaneous and visceral adiposity (Grobe et al, 2010).…”

“…Induces a profound reduction in both subcutaneous and visceral adiposity (Grobe et al, 2010). Leads to enhanced brown adipose tissue thermogenesis and white adipose tissue lipolysis, possibly through AT2 receptor (Watanabe et al, 1999;de Kloet et al, 2011).…”

Editorial Focus: A fat contribution to RAS activation and blood pressure control: evidence from angiotensinogen conditional null mice. Focus on: “Adipocyte-specific deficiency of angiotensinogen decreases plasma angiotensinogen concentration and systolic blood pressure in mice.”

“…Previous investigations into the role of the RAS in metabolic control have demonstrated substantial reductions in adiposity and body mass, altered adipose morphology, increases in metabolic rate, decreased food intake, and/or altered glucose homeostasis in global RAS knockout models (or in wild-type animals following pharmacological inhibition) of renin, AGT, ACE, AT1A receptors, AT2 receptors, and Mas receptors (9). Furthermore, studies investigating the effects of brain versus peripheral RAS signaling have underscored opposing roles for brain versus peripheral RAS in metabolic control (1,3). Thus, the present study adds to this line of investigation by highlighting a surprisingly minimal role for adipose-derived AGT in RAS-mediated metabolic control.…”

Renin–angiotensin–aldosterone system in insulin resistance and metabolic syndrome

“…Ang-II acts in the brain to promote negative energy balance by altering the hypothalamic circuits regulating energy balance that include increased uncoupling protein-1 and β(3)-adrenergic receptor expression in brown adipose tissue and β3-adrenergic receptor expression in white adipose tissue, suggesting enhanced sympathetic activation and thermogenesis; decrease food intake, increase in energy expenditure [47] , and finally Ang II type-1a receptor-dependent Ang-II signaling reduces food intake by suppressing the hypothalamic expression of neuropeptide Y and orexins via AMPK dephosphorylation [48] .…”