Carolien Elyse Geisler

Glia play a dynamic role in central nutrient sensing and appetite regulation yet represent underexplored targets in treating dysregulated energy balance. Glia within the dorsal vagal complex of the hindbrain synthesize the anorexigenic peptide octadecaneuropeptide (ODN), the influence and therapeutic potential of which remain to be explored. We demonstrate that hindbrain-targeted ODN induced weight loss, counteracted glucoprivation, and improved glucose clearance in rats. Furthermore, blocking central ODN signaling attenuated the anorectic response to GLP-1R agonists in rats. Peripheral administration of an ODN derivative, TDN, improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp in obese mice and induced weight loss without pica behavior, a proxy for nausea in rats, or emesis in the musk shrew, a vomiting mammalian model. Central ODN and TDN treatment in rats was not accompanied by changes in core body temperature, physical activity, or heart rate. This work highlights hindbrain ODN signaling as an important modulator of energy balance and demonstrates the potential for targeting this gliopeptide system to treat dysregulated feeding and metabolic activity without side effects.

Circadian desynchrony induced by shiftwork or jet lag is detrimental to metabolic health, but how synchronous or desynchronous signals are transmitted among tissues is unknown. We report that liver molecular clock dysfunction is signaled to the brain through the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain. Our findings reveal a homeostatic feedback signal that relies on communication between the liver and the brain to control circadian food intake patterns. This identifies the hepatic vagus nerve as a potential therapeutic target for obesity in the setting of chronodisruption.

Circadian desynchrony induced by shiftwork or jetlag is detrimental to metabolic health, but how synchronous/desynchronous signals are transmitted among tissues is unknown. Here we report that liver molecular clock dysfunction is signaled to the brain via the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain. Our findings reveal a previously unrecognized homeostatic feedback signal that relies on synchrony between the liver and the brain to control circadian food intake patterns. This identifies the hepatic vagus nerve as a therapeutic target for obesity in the setting of chrono-disruption. One Sentence Summary: The hepatic vagal afferent nerve signals internal circadian desynchrony between the brain and liver to induce maladaptive food intake patterns.

Aim: To investigate the role of glucose‐dependent insulinotropic polypeptide receptor (GIPR) agonists alone or combined with glucagon‐like peptide‐1 receptor (GLP‐1R) agonists to regulate palatable food intake and the role of specific macronutrients in these preferences. Methods: To understand this regulation, we treated mice and rats on several choice diet paradigms of chow and a palatable food option with individual or dual GIPR and GLP‐1R agonists. Results: In mice, the dual agonist tirzepatide suppressed total caloric intake, while promoting the intake of chow over a high fat/sucrose diet. Surprisingly, GIPR agonism alone did not alter food choice. The food intake shift observed with tirzepatide in wild‐type mice was completely absent in GLP‐1R knockout mice, suggesting that GIPR signalling does not regulate food preference. Tirzepatide also selectively suppressed the intake of palatable food but not chow in a rat two‐diet choice model. This suppression was specific to lipids, as GLP‐1R agonist and dual agonist treatment in rats on a choice paradigm assessing individual palatable macronutrients robustly inhibited the intake of Crisco (lipid) without decreasing the intake of a sucrose (carbohydrate) solution. Conclusions: Decreasing preference for high‐caloric, high‐fat foods is a powerful action of GLP‐1R and dual GIPR/GLP‐1R agonist therapeutics, which may contribute to the weight loss success of these drugs.

Loss of SCN REV-ERBs alters oscillator period but does not render the clock arrhythmic.

Signaling through GPR109a, the putative receptor for the endogenous ligand β-OH butyrate, inhibits adipose tissue lipolysis. Niacin, an anti-atherosclerotic drug that can induce insulin resistance, activates GPR109a at nM concentrations. GPR109a is not essential for niacin to improve serum lipid profiles. To better understand the involvement of GPR109a signaling in regulating glucose and lipid metabolism, we treated GPR109a wild-type (+/+) and knockout (−/−) mice with repeated overnight injections of saline or niacin in physiological states characterized by low (ad libitum fed) or high (16 h fasted) concentrations of the endogenous ligand, β-OH butyrate. In the fed state, niacin increased expression of apolipoprotein-A1 mRNA and decreased sterol regulatory element-binding protein 1 mRNA independent of genotype, suggesting a possible GPR109a independent mechanism by which niacin increases high-density lipoprotein (HDL) production and limits transcriptional upregulation of lipogenic genes. Niacin decreased fasting serum non-esterified fatty acid concentrations in both GPR109a +/+ and −/− mice. Independent of GPR109a expression, niacin blunted fast-induced hepatic triglyceride accumulation and peroxisome proliferator-activated receptor α mRNA expression. Although unaffected by niacin treatment, fasting serum HDL concentrations were lower in GPR109a knockout mice. Surprisingly, GPR109a knockout did not affect glucose or lipid homeostasis or hepatic gene expression in either fed or fasted mice. In turn, GPR109a does not appear to be essential for the metabolic response to the fasting ketogenic state or the acute effects of niacin.

Obesity occurs when energy expenditure is outweighed by energy intake. Tuberal hypothalamic nuclei, including the arcuate nucleus (ARC), ventromedial nucleus (VMH), and dorsomedial nucleus (DMH), control food intake and energy expenditure. Here we report that, in contrast with females, male mice lacking circadian nuclear receptors REV-ERBα and –β in the tuberal hypothalamus (HDKO mice) gained excessive weight on an obesogenic high-fat diet due to both decreased energy expenditure and increased food intake during the light phase. Moreover, rebound food intake after fasting was markedly increased in HDKO mice. Integrative transcriptomic and cistromic analyses revealed that such disruption in feeding behavior was due to perturbed REV-ERB–dependent leptin signaling in the ARC. Indeed, in vivo leptin sensitivity was impaired in HDKO mice on an obesogenic diet in a diurnal manner. Thus, REV-ERBs play a crucial role in hypothalamic control of food intake and diurnal leptin sensitivity in diet-induced obesity.

Signaling through GPR109a, the putative receptor for the endogenous ligand β-OH butyrate, inhibits adipose tissue lipolysis. Niacin, an anti-atherosclerotic drug that can induce insulin resistance, activates GPR109a at nM concentrations. GPR109a is not essential for niacin to improve serum lipid profiles. To better understand the involvement of GPR109a signaling in regulating glucose and lipid metabolism, we treated GPR109a wildtype (+/+) and knockout (-/-) mice with repeated overnight injections of saline or niacin in physiological states characterized by low (ad libitum fed) or high (16h fasted) concentrations of the endogenous ligand, β-OH butyrate. In the fed state, niacin increased expression of PEPCK mRNA independent of genotype, while increasing CPT1 mRNA only in GPR109a -/- mice. Niacin decreased fasting serum non-esterified fatty acid concentrations in both GPR109a +/+ and -/- mice. Independent of GPR109a expression, niacin blunted fast-induced hepatic triglyceride accumulation and peroxisome proliferator activated receptor α (PPARα) mRNA expression. Surprisingly, GPR109a knockout did not affect glucose or lipid homeostasis or hepatic gene expression in either fed or fasted mice. In turn, GPR109a does not appear to be essential for the metabolic response to the ketogenic state or the pharmacological benefits associated with niacin.