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The liver regulates energy partitioning and utilization in a sex-dependent manner, coupling hepatic substrate availability to female reproductive status. Fibroblast growth factor-21 (FGF21) is a hepatokine produced in response to metabolic stress that adaptively directs systemic metabolism and substrate utilization to reduce hepatic lipid storage. Here we report that FGF21 alters hepatic transcriptional and metabolic responses, and reduces liver triglycerides, in a sex-dependent manner. FGF21 decreased hepatic triglycerides in obese male mice in a weight loss-independent manner; this was abrogated among female littermates. The effect of FGF21 on hepatosteatosis is thought to derive, in part, from increased adiponectin secretion.Accordingly, plasma adiponectin and its upstream adrenergic receptor à cAMP à EPAC1 signaling pathway was stimulated by FGF21 in males and inhibited in females. Both ovariectomized and reproductively senescent, old females responded to FGF21 treatment by decreasing body weight, but liver triglycerides and adiponectin remained unchanged. Thus, the benefit of FGF21 treatment for improving hepatosteatosis depends on sex, but not on a functional female reproductive system. Because FGF21 provides a downstream mechanism contributing to several metabolic interventions, and given its direct clinical importance, these findings may have broad implications for the targeted application of nutritional and pharmacological treatments for metabolic disease.

Long-acting glucagon-like peptide 1 receptor (GLP1R) agonists are currently the most effective pharmacotherapies for weight loss, although adverse effects (e.g., nausea and vomiting) limit treatment efficacy. What brain circuits do these pharmacotherapies engage to reduce body weight? Our data demonstrate that acute chemogenetic activation of GLP1R neurons in the hindbrain dorsal vagal complex (DVC) suppressed food intake (p<0.001), and chronic activation of GLP1RDVC neurons attenuated weight gain in high-fat diet-fed mice (p<0.001). Here, we sought to determine whether there are separable subpopulations of hindbrain GLP1RDVC neurons that mediate satiety and adverse effects (i.e., nausea). To determine whether GLP1RDVC neurons cause nausea-like behavior, we tested if GLP1RDVC neuron activation conditions a taste avoidance or aversive orofacial taste reactivity responses. Activation of GLP1RDVC neurons both conditioned a robust taste avoidance (p<0.001) and aversive taste reactivity responses (p<0.001), which was strikingly correlated to activation of GLP1R neurons in the area of postrema (AP, R2=0.545), but not in the nucleus of solitary tract (NTS, R2=0.036), which are both subregions of the DVC. These data raised the possibility that there are discrete anatomical subpopulations of GLP1RDVC neurons within the DVC that have dissociable effects on behavior. Indeed, while activation of either GLP1RAP or GLP1RNTS neurons reduced food intake (p<0.001), only activation of GLP1RAP neurons induced a conditioned taste avoidance (p<0.001). To determine the downstream projection of GLP1RAP and GLP1RNTS neurons, we used two complementary approaches: (1) virally-expressed fluorophore tracing to label axonal projections, and (2) pseudorabies virus (PRV) to retrogradely label distinct populations of GLP1RDVC neurons. Results from both experiments demonstrated that the two subpopulations have parallel projections, where GLP1RAP neurons project to the lateral parabrachial nucleus (lPBN) and GLP1RNTS neurons project to the paraventricular hypothalamus (PVH). To test the functional relevance of these parallel GLP1RDVC projections, we optogenetically activated axonal terminals of GLP1RDVC neurons in either the lPBN or the PVH. Activation of the terminals in either lPBN or PVH suppressed food intake (p<0.01), but only activation of lPBN terminals induced avoidance (p<0.01). These data demonstrate that there are two anatomically- and functionally-discrete subpopulations of GLP1RDVC neurons, where GLP1RNTS->PVH neurons mediate satiety and GLP1RAP->lPBN neurons induce nausea. Moving forward, targeting obesity therapeutics to neuron populations that suppress food intake without nausea will increase treatment adherence and facilitate more effective long-term weight loss. American Heart Association 898990 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Fibroblast growth factor-21 (FGF21) decreases hepatic triglycerides when administered to obese animals and humans, and thus has gained attention as a novel drug target for nonalcoholic fatty liver disease (NAFLD). However, its mechanism of action remains unclear. Furthermore, although NAFLD pathology is well known to be sexually dimorphic, studies of FGF21 have skewed toward males without sufficient consideration of sex as a biological variable. Here we report that FGF21 administration to diet-induced obese mice decreased hepatic triglycerides in a weight loss-independent manner in obese male mice, but this effect was blunted in female littermates (p(treatment x sex)&lt;0.001). Adiponectin, a key mediator of FGF21’s therapeutic effects, was increased by FGF21 in males but not females (p(treatment x sex)&lt;0.01). In agreement with this, FGF21 elicited an increase in hepatic adenosine monophosphate, known to be downstream of adiponectin signaling, and decreased the expression of lipogenic genes Pparg, Cidea, and Cd36 in males but not females (p(treatment x sex)&lt;0.05, &lt;0.0001, &lt;0.05, &lt;0.01, respectively). Finally, we investigated whether the metabolic benefits of FGF21 observed in males are restored in ovariectomized (OVX) females. OVX females did not phenocopy males, as FGF21 did not significantly decrease hepatic triglycerides, increase plasma adiponectin, or decrease lipogenic gene expression in OVX females. These data have immediate clinical implications, and highlight the importance of both sex and reproductive status as a biological variable in ongoing development of FGF21-based therapeutics for NAFLD. Disclosure A. T. B. Chaffin: None. K. R. Larson: None. K. Huang: None. K. K. Ryan: None. Funding National Institutes of Health (R01DK121035, F31DK124080)