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Adipose Tissue_Appetite_and Obesity

SUN-677 - Β₁-Adrenergic Blockade Preserves the Metabolic Benefits of Β₃-Adrenergic Agonism without Raising Blood Pressure

Sunday, June 14, 2026
9:00 AM - 4:00 PM CT
Location: ENDOExpo; Poster Floor
Disclosure(s):
Omprakash Singh, PhD: No financial relationships to disclose
Abstract

Background: The sympathetic nervous system (SNS) plays a critical role in controlling adipose tissue function, with many of these effects attributed to norepinephrine activation of the β3- adrenergic receptor (β3-AR). However, global deletion of Adrb3 in mice does not affect basal metabolic rate or adaptive responses to cold and diet-induced obesity, suggesting that additional adrenergic receptors may be important. One such candidate is the β1-adrenergic receptor (β1-AR). Here, we investigated the physiological relevance of crosstalk between ADRB1 and ADRB3 in adipocytes, including the potential of combining an β3-AR agonist with an β1-AR antagonist to treat metabolic syndrome.

Methods: Adiponectin (Adipoq)-Cre mice were crossed with loxP-flanked Adrb1 (Adrb1flox/flox) mice. The resulting Ad-Adrb1KO mice, which selectively lack Adrb1 from adipocytes, and Adrb1flox/flox controls were evaluated for diet-induced obesity susceptibility, cold tolerance, and glucose tolerance in response to administered selective β3-AR agonist (CL 316,243). Separately, the effects of another β3-AR agonist (Mirabegron)  β1-AR antagonist (Atenolol) administration for 4 weeks on body weight-related, glycemic, and cardiovascular parameters were determined in high-fat diet-fed C57BL/6N mice housed at room temperature and at thermoneutrality.

Results: Adipocyte-specific deletion of Adrb1 did not affect the susceptibility to diet-induced obesity or tolerance to cold exposure but resulted in increased brown adipose tissue mass and enhanced sensitivity to β3-AR agonism. Specifically, CL 316,243 produced greater reductions in blood glucose, increased insulin levels, and improved insulin sensitivity in Ad-Adrb1KO mice. In diet-induced obese mice, high-dose Mirabegron limited body weight and fat mass gain, lowered total and LDL cholesterol, and improved glucose tolerance. Combining Atenolol with Mirabegron did not further improve those parameters but prevented Mirabegron-induced increases in blood pressure.

Conclusions: These findings identify coordinated actions of β1-AR and β3-AR within adipose tissue as key regulators of systemic glucose homeostasis. Disrupting β1-AR signaling sensitizes adipose tissue to β3-AR-driven metabolic effects, revealing a previously unrecognized therapeutic opportunity. While high-dose β3-AR agonism alone is limited by adverse cardiovascular effects, combining an β1-AR antagonist with an β3-AR agonist could not only enhance the metabolic benefits of β3-AR, but also while prevent hypertension, supporting this strategy as a potential treatment approach for obesity-related cardiometabolic syndrome.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*