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Estrogens favor glucose homeostasis primarily through the estrogen receptor-α (ERα), but the respective importance of nuclear ERα (NOER) and membrane ERα (MOER) pools to glucose homeostasis are unknown. We studied glucose homeostasis, insulin secretion, and insulin sensitivity in male and female mice expressing either the NOER or the MOER. Male and female MOER mice exhibited fasting and fed hyperglycemia and glucose intolerance. Female MOER mice displayed impaired central insulin signaling associated with hyperinsulinemia and insulin resistance due to unrestrained hepatic gluconeogenesis, without alterations in glucose-stimulated insulin secretion (GSIS). In contrast, male MOER mice did not exhibit detectable insulin resistance, but showed impaired GSIS associated with reduced brain glucose sensing. Female NOER mice exhibited milder hepatic insulin resistance and glucose intolerance. In conclusion, nuclear ERα signaling is predominant in maintaining glucose homeostasis in mice of both sexes. Lack of nuclear ERα alters the central control of insulin sensitivity in females and predominantly impairs the central regulation of insulin secretion in males.

Glucagon-like peptide 1 receptor (GLP-1R) agonists effectively improve glycemia and body weight in patients with type 2 diabetes and obesity but have limited weight-lowering efficacy and minimal insulin sensitizing action. In preclinical models, peripherally restricted cannabinoid receptor type 1 (CB1R) inhibitors, which are devoid of the neuropsychiatric adverse effects observed with brain-penetrant CB1R blockers, ameliorate obesity and its multiple metabolic complications. Using mouse models with genetic loss of CB1R or GLP-1R, we demonstrate that these two metabolic receptors modulate food intake and body weight via reciprocal functional interactions. In diet-induced obese mice, the coadministration of a peripheral CB1R inhibitor with long-acting GLP-1R agonists achieves greater reduction in body weight and fat mass than monotherapies by promoting negative energy balance. This cotreatment also results in larger improvements in systemic and hepatic insulin action, systemic dyslipidemia, and reduction of hepatic steatosis. Thus, peripheral CB1R blockade may allow safely potentiating the antiobesity and antidiabetic effects of currently available GLP-1R agonists. [ABSTRACT FROM AUTHOR]