Editors' ChoiceObesity

Worth its salt

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Science Translational Medicine  05 Apr 2017:
Vol. 9, Issue 384, eaan2774
DOI: 10.1126/scitranslmed.aan2774


Angiotensin type 1 receptors are required for leptin-mediated control of resting metabolic rate but not blood pressure.

Leptin is a hormone produced by adipose tissue that acts centrally to control energy homeostasis and is a well-known modulator of resting metabolic rate (RMR) and blood pressure. In obesity, leptin resistance in the central nervous system blunts leptin’s ability to increase RMR without affecting blood pressure. The underlying mechanism for this selective resistance is unknown.

Clafin et al. investigated the interaction between the renin-angiotensin system (the main endocrine regulator of blood pressure) and leptin receptor/agouti-related peptide (AgRP)–expressing neurons in the arcuate nucleus region of the hypothalamus in the brains of mice. First, they demonstrated that a subset of leptin receptor–expressing neurons in the arcuate nucleus also express angiotensin type 1 receptors. The investigators then created a transgenic mouse that lacked the angiotensin type 1 receptor in cells expressing the leptin receptor. When these transgenic mice were treated with deoxycorticosterone acetate and a high-salt diet (DOCA salt model) to induce hypertension, there was a typical increase in blood pressure but a blunted increase in RMR. This relationship was unidirectional, as leptin receptor–deficient animals exposed to the DOCA salt model demonstrated the expected increase in both RMR and blood pressure. Similar results were seen with decreased expression of the angiotensin type 1 receptor in AgRP-expressing neurons. The investigators concluded that angiotensin II acts on angiotensin type 1 receptors in a subset of leptin receptor/AgRP–expressing hypothalamic neurons. Functional angiotensin 1 receptors are required for angiotensin II and leptin to increase RMR but not blood pressure.

This study highlights the underappreciated role of the renin-angiotensin system in central control of energy homeostasis. This role appears to be specific to the control of RMR and begins to explain selective leptin resistance. Unraveling the molecular control of energy balance is critical to efforts to develop pharmacotherapeutics for obesity that induce weight loss without undesirable cardiovascular effects, such as hypertension.

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