👤 Hayley E McMorrow

The incretin receptor agonists semaglutide and tirzepatide have transformed the medical management of obesity. The neural mechanisms by which incretin analogs regulate appetite remain incompletely understood, and dissecting this process is critical for the development of next-generation antiobesity drugs that are more targeted and tolerable. Moreover, the physiologic functions of incretins in appetite regulation and gut-brain communication have remained elusive. Using in vivo fiber photometry, we discovered distinct pharmacologic and physiologic roles for the incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We showed that GIP, but not GLP-1, was required for normal nutrient-mediated inhibition of hunger-promoting AgRP neurons. By contrast, both GIP and GLP-1 analogs at pharmacologic doses were sufficient to inhibit AgRP neurons. The magnitude of neural inhibition was proportional to the effect of each incretin on food intake, and dual GIP and GLP-1 receptor agonism more potently inhibited AgRP neurons and suppressed food intake than either agonist alone. Our results have revealed a role for endogenous GIP in gut-brain appetite regulation and indicate that incretin analogs act in part via AgRP neurons to mediate their anorectic effects. Show less

Patients experiencing premature cardiovascular events (males: <55 years; females: <65 years) represent a high-risk subgroup within the atherosclerotic cardiovascular disease (ASCVD) population. Elevated lipoprotein(a) (Lp[a]) is an independent, genetic, causal risk factor for ASCVD. Lp(a) distribution among patients with premature ASCVD is poorly characterized. This study aimed to describe Lp(a) distribution and baseline characteristics in a large real-world sample of patients with premature ASCVD. We identified 17,594 patients with premature ASCVD who had Lp(a) values from US Medicare, Medicaid, and commercial plans between January 2016-September 2022. Mean age (SD) was 50.9 (10.1) years, most patients were female (68.9%), and half (52.2%) were not prescribed lipid-lowering therapy. Lp(a) levels ≥125, ≥175, and ≥225 nmol/L occurred in 26.8%, 18.8%, and 11.5%, respectively. Black patients had higher median (Q1-Q3) Lp(a) levels (111.0 [51.1-206.0] nmol/L) than Asian (35.0 [14.4-100.0] nmol/L), Hispanic (31.0 [10.9-95.0] nmol/L), or White patients (31.0 [10.7-110] nmol/L). In one of the largest studies in the US investigating Lp(a) distribution in premature ASCVD, we found over a quarter of patients had elevated Lp(a) (≥125 nmol/L). Show less

Analogs of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have become mainstays of obesity and diabetes management. However, both the physiologic role of incretin hormones in the control of appetite and the pharmacologic mechanisms by which incretin-mimetic drugs suppress caloric intake remain incompletely understood. Hunger-promoting AgRP-expressing neurons are an important hypothalamic population that regulates food intake. Therefore, we set out to determine how incretins analogs affect their activity Show less