Chow Intake Research Articles

Ventral tegmental area amylin / calcitonin receptor signaling suppresses feeding and weight gain in female rats

The pancreatic peptide amylin promotes negative energy balance in part through activation of amylin receptors (AmyRs) expressed in the ventral tegmental area (VTA), but studies have been limited to male rodents. We evaluated whether VTA amylin signaling governs feeding and body weight in female rats. Indeed, pharmacological VTA AmyR activation suppressed chow intake and body weight in females. Viral-mediated knockdown of VTA calcitonin receptor (GPCR of AmyR) supports the physiological relevance of VTA amylin signaling for energy balance control in females. Collectively, these data support the relevance of VTA amylin signaling for energy balance control in both sexes.

The Investigation of The Metabolic Effect of High Salt or Western Diet During Pregnancy and Lactation on Rat Dams and Postnatal Offspring Rats

Objective: This study investigated the metabolic effect of maternal high-salt and western low-protein diets during pregnancy and lactation periods on rat dams and adult offspring. Methods: Female rat dams were divided into four groups and fed with a 1% high salt diet, a Western low-protein diet (high fat and sugar and low protein), or a 1% high salt/western low-protein combined diet (WS) during pregnancy and lactation. Afterward, 95 female and male offspring were divided into groups and fed with those diets until 18 weeks of age. The mothers’ and offspring rats' body weights and chow intake were recorded periodically. At 18 weeks of age, blood samples were collected from the offspring. Their blood lipid profiles, leptin, and insulin levels were analyzed. Results: Rat dams had similar weight changes during pregnancy and lactation. Rats exposed to the Western low-protein and WS diet during pregnancy, lactation, and/or postweaning had lower body weights than the control group. Male adult offspring from control dams and fed high salt were heavier and had higher LDL cholesterol than controls. However, rats from high salt dams and fed a high salt diet had lower body weights than the control group. Plasma insulin and leptin of male rats were not significantly different. Female offspring fed Western low-protein and WS diet in the fetal period or in early childhood had significantly low insulin. However, female rats exposed to Western low-protein and WS diets during pregnancy, lactation, and postweaning had similar insulin to control rats. Conclusion: Maintaining the maternal diet after lactation prevents the detrimental effect of a low-protein diet on insulin levels. Anti-obesity mechanism may develop in offspring exposed to a high salt diet during the fetal period against salt intake in later life.

Pharmacological characterization of sex differences in the effects of dopaminergic drugs on effort-based decision making in rats.

Motivational dysfunctions related to effort exertion are common in psychiatric disorders. Dopamine systems regulate exertion of effort and effort-based choice in humans and rodents. Previous rodent studies mainly employed male rats, and it is imperative to conduct studies in male and female rats. The present studies compared the effort-related effects of IP injections of the dopamine antagonists ecopipam and haloperidol, and the vesicular monoamine transport-2 inhibitor tetrabenazine (TBZ), in male and female rats using the fixed ratio 5/chow feeding choice task. Ecopipam (0.05-0.2mg/kg) and haloperidol (0.05-0.15mg/kg) induced a low-effort bias, decreasing lever pressing and increasing chow intake in males and females in the same dose range. With lever pressing, there was a modest but significant dose x sex interaction after ecopipam injection, but there was no significant interaction after administration of haloperidol. In the first study with TBZ (0.25-1.0mg/kg), there was a robust sex difference. TBZ shifted choice from lever pressing to chow intake in male rats, but was ineffective in females. In a second experiment, 2.0mg/kg affected choice behavior in both males and females. TBZ increased accumbens c-Fos immunoreactivity in a sex-dependent manner, with males significantly increasing at 1.0mg/kg, while females showed augmented immunoreactivity at 2.0mg/kg. The neural and behavioral effects of TBZ differed across sexes, emphasizing the importance of conducting studies in male and female rats. This research has implications for understanding the effort-related motivational dysfunctions seen in psychopathology.

Chronic pramlintide decreases feeding via a reduction in meal size in male rats

Amylin, a pancreatic hormone, is well-established to suppress feeding by enhancing satiation. Pramlintide, an amylin analog that is FDA-approved for the treatment of diabetes, has also been shown to produce hypophagia. However, the behavioral mechanisms underlying the ability of pramlintide to suppress feeding are unresolved. We hypothesized that systemic pramlintide administration in rats would reduce energy intake, specifically by reducing meal size. Male rats were given b.i.d. administration of intraperitoneal pramlintide or vehicle for 1 week, and chow intake, meal patterns, and body weight were monitored throughout the test period. Consistent with our hypothesis, pramlintide decreased chow intake mainly via suppression of meal size, with corresponding reductions in meal duration on several days. Fewer effects on meal number or feeding rate were detected. Pramlintide also reduced weight gain over the 1-week study. These results highlight that the behavioral mechanisms by which pramlintide produces hypophagia are similar to those driven by amylin itself, and provide important insight into the ability of this pharmacotherapy to promote negative energy balance over a period of chronic administration.

Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors.

People with depression and other neuropsychiatric disorders can experience motivational dysfunctions such as fatigue and anergia, which involve reduced exertion of effort in goal-directed activity. To model effort-related motivational dysfunction, effort-based choice tasks can be used, in which rats can select between obtaining a preferred reinforcer by high exertion of effort vs. a low effort/less preferred option. Preclinical data indicate that dopamine transport (DAT) inhibitors can reverse pharmacologically-induced low-effort biases and increase selection of high-effort options in effort-based choice tasks. Although classical DAT blockers like cocaine can produce undesirable effects such as liability for misuse and psychotic reactions, not all DAT inhibitors have the same neurochemical profile. The current study characterized the effort-related effects of novel DAT inhibitors that are modafinil analogs and have a range of binding profiles and neurochemical actions (JJC8-088, JJC8-089, RDS3-094, and JJC8-091) by using two different effort-related choice behavior tasks in male Sprague-Dawley rats. JJC8-088, JJC8-089, and RDS3-094 significantly reversed the low-effort bias induced by the VMAT-2 inhibitor tetrabenazine, increasing selection of high-effort fixed ratio 5 lever pressing vs. chow intake. In addition, JJC8-089 reversed the effects of tetrabenazine in female rats. JJC8-088 and JJC8-089 also increased selection of high-effort progressive ratio responding in a choice task. However, JJC8-091 failed to produce these outcomes, potentially due to its unique pharmacological profile (i.e., binding to an occluded conformation of DAT). Assessment of a broad range of DAT inhibitors with different neurochemical characteristics may lead to the identification of compounds that are useful for treating motivational dysfunction in humans.

GLP-1 receptor agonist semaglutide reduces appetite while increasing dopamine reward signaling

Semaglutide, a glucagon-like peptide-1 receptor agonist, is an effective drug reducing body weight and decreasing motivation for palatable food. The mechanisms underlying its effects on food reward remain unclear. We aimed to determine the impact of semaglutide on food reward collection and dopamine-neuron activity in the ventral tegmental area (VTA) upon exposure to a cue-induced sucrose delivery task.Pitx3-cre mice were injected with cre-dependent GCaMP6s virus into the VTA, to measure the activity of dopaminergic neurons in the VTA using in vivo fiber photometry. Mice were trained on a Pavlovian sucrose conditioning paradigm in which a 5-s cue signaled a 20% sucrose reward. Upon stable performance, semaglutide or vehicle was intraperitoneally injected during the task.1 mg/kg semaglutide reduced the number of collected rewards and licks during the task. Semaglutide increased VTA dopamine neuron activity during sucrose collection but not during the cue. Lower doses of semaglutide (0.1 and 0.3 mg/kg) reduced chow intake but not sucrose intake nor VTA dopamine activity in the task.Semaglutide reduces appetite but increases VTA dopamine signaling during reward collection. Semaglutide does not influence dopamine signaling during the presentation of food cues.

From the stomach to locus coeruleus: new neural substrate for ghrelin's effects on ingestive, motivated and anxiety-like behaviors.

Ghrelin, a stomach-derived orexigenic hormone, has a well-established role in energy homeostasis, food reward, and emotionality. Noradrenergic neurons of the locus coeruleus (LC) are known to play an important role in arousal, emotion, cognition, but recently have also been implicated in control of feeding behavior. Ghrelin receptors (the growth hormone secretagogue receptor, GHSR) may be found in the LC, but the behavioral effects of ghrelin signaling in this area are still unexplored. Here, we first determined whether GHSR are present in the rat LC, and demonstrate that GHSR are expressed on noradrenergic neurons in both sexes. We next investigated whether ghrelin controls ingestive and motivated behaviors as well as anxiety-like behavior by acting in the LC. To pursue this idea, we examined the effects of LC GHSR stimulation and blockade on food intake, operant responding for a palatable food reward and, anxiety-like behavior in the open field (OF) and acoustic startle response (ASR) tests in male and female rats. Our results demonstrate that intra-LC ghrelin administration increases chow intake and motivated behavior for sucrose in both sexes. Additionally, females, but not males, exhibited a potent anxiolytic response in the ASR. In order to determine whether activation of GHSR in the LC was necessary for feeding and anxiety behavior control, we utilized liver-expressed antimicrobial peptide 2 (LEAP2), a newly identified endogenous GHSR antagonist. LEAP2 delivered specifically into the LC was sufficient to reduce fasting-induced chow hyperphagia in both sexes, but food reward only in females. Moreover, blockade of GHSR in the LC increased anxiety-like behavior measured in the ASR test in both sexes. Taken together, these results indicate that ghrelin acts in the LC to alter ingestive, motivated and anxiety-like behaviors, with a degree of sex divergence.

Sex-divergent effects of hindbrain GLP-1-producing neuron activation in rats.

Glucagon-like peptide-1 (GLP-1) analogs represent a new class of weight-loss medication, which has recently exponentially grown in popularity. GLP-1 is produced in the intestinal L cells in response to macronutrient intake, but it is also produced in the brain in a subset of neurons in the nucleus of the solitary tract (NTS). Exogenously-delivered GLP-1 analogs reduce food intake and food-motivated behavior in male and female rats, with some sex divergence of these effects in specific brain sites. These analogs potentially target GLP-1 receptors endogenously supplied by the gut and brain-produced GLP-1. The function of the NTS GLP-1-producing neurons [Gcg neurons] is still relatively unknown in rats. Moreover, even less is understood about the function of these neurons in females. We have recently developed a transgenic rat that expresses Cre under the Gcg promoter. Here, we interrogate this new animal model with optogenetics and chemogenetics to determine whether activation of the NTS GLP-1 neurons affects ingestive and motivated behavior in male and female rats. Optogenetic activation of the NTS Gcg neurons robustly reduced chow intake in both male and female rats. Interestingly, motivated behavior for a sucrose reward was reduced exclusively in females. To ensure that this unexpected sex difference was not activation method-specific, we next virally introduced excitatory DREADD receptors into the Gcg neurons and investigated the effect of chemogenetic activation of these neurons on ingestive and motivated behavior. Even upon chemogenetic activation, female rats reduced their motivation to obtain the sucrose reward, yet no effect on this behavior was observed in males. Our results show that activation of hindbrain Gcg neurons is sufficient to reduce food intake in both sexes. In females, but not males, Gcg neuron activation alone is also sufficient to reduce motivated behavior for sucrose. Thus, there is a sex difference in the ability of GLP-1-producing neuron activation to control motivated behavior for food.

Effort-related effects of chronic administration of the DA D2 receptor antagonist haloperidol via subcutaneous programmable minipumps: Reversal by co-administration of the adenosine A2A antagonist istradefylline.

Long-acting antipsychotics such as haloperidol decanoate are becoming more commonly used. Long-acting depot formulations have several advantages, but secondary negative effects of prolonged delivery, including motivational dysfunctions, could have debilitating effects. Assessing the behavioral changes that emerge during chronic antipsychotic administration in rats could provide insight regarding the development of motivational dysfunctions and drug tolerance. Acute administration of dopamine D2 antagonists such as haloperidol induce motivational deficits in rats, as marked by a shift towards a low-effort bias during effort-based choice tasks. In the present studies, programmable subcutaneous infusion pumps provided continuous and controlled drug delivery of haloperidol. Animals were assessed using a fixed ratio (FR) 5 lever pressing schedule and the FR5/chow feeding test of effort-based choice. The adenosine A2A antagonist istradefylline was studied for its ability to reverse the effects of chronic haloperidol. Continuous chronic infusions of haloperidol produced significant reductions in FR5 performance and a shift from lever pressing to chow intake in rats tested on FR5/chow feeding choice, with no evidence of tolerance over the 4-week infusion period. Behavior returned to baseline during the vehicle-infusion washout period. Istradefylline significantly reversed the effects of haloperidol, increasing lever pressing and decreasing chow intake in haloperidol-treated rats. These studies provide an important behavioral characterization of the effects of chronically infused haloperidol, and demonstrate that A2A antagonism reverses the effects of chronic haloperidol. This research could contribute to the understanding and treatment of motivational dysfunctions seen in schizophrenia, Parkinson's disease, and other disorders involving dopamine.

Effect of intranasal oxytocin on palatable food consumption and c-Fos immunoreactivity in relevant brain areas in rats

Peripheral and central injections of oxytocin (OT) in laboratory animals decrease eating for energy and palatability, but the hypophagic response is dependent on the administration route. Human studies rely on intranasal (IN) administration of the peptide, the route underutilized in OT animal feeding studies thus far. Therefore, we examined the effect of IN OT on various aspects of food consumption in rats: (a) overnight deprivation-induced standard chow intake, (b) episodic (2-h) consumption of calorie-dense and palatable high-fat high-sugar (HFHS) chow, (c) 2-h episodic intake of palatable and calorie-dilute sucrose and Intralipid solutions, and (d) 2-h sucrose solution intake in rats habituated to ingesting this solution daily for several weeks. Finally, we assessed c-Fos changes in response to the acute IN OT administration in rats habituated to daily sugar consumption. We found that IN 20μg OT decreased deprivation-induced intake of standard chow and HFHS chow in nondeprived rats without affecting water consumption. IN OT also reduced 2-hour episodic fluid consumption of sucrose, but not Intralipid. In the habitual sugar consumption paradigm, acute IN OT diminished sucrose solution intake in animals accustomed to the 2-hour/day sucrose meal regimen. In rats habitually consuming sucrose, IN OT altered c-Fos immunoreactivity in brain areas related to energy homeostasis and reward, including the central nucleus of the amygdala, the hypothalamic paraventricular and the arcuate nuclei. We conclude that IN OT is an effective appetite suppressant for carbohydrate/sugar diets in rats and its effects involve feeding-related brain circuits.

Effects of the atypical antipsychotic and D3/D2 dopamine partial agonist cariprazine on effort-based choice behavior: implications for modeling avolition.

Cariprazine is an atypical antipsychotic that acts as a D3/D2 receptor partial agonist. In addition to treating positive symptoms of schizophrenia, cariprazine may have utility for treating negative symptoms. Rodent studies have focused on the effects of cariprazine on cognitive functions and behaviors thought to be related to anhedonia. Avolition, which is characterized by reduced initiation and persistence of goal-directed behavior, is another important negative symptom. Effort-related choice tasks have been used as animal models of avolition. In these studies, cariprazine was assessed for its effects on effort-based choice in both rats and mice. Previous work has shown that D2 antagonists such as haloperidol and eticlopride produce a low-effort bias in rodents tested on effort-based choice tasks. Low doses of cariprazine produced a low-effort bias in rats tested on the fixed ratio 5/chow feeding choice task, decreasing lever pressing for high carbohydrate pellets but increasing chow intake. Cariprazine did not alter preference or intake of these foods in free-feeding tests. The effort-related effects of cariprazine were reversed by co-administration of the adenosine A2A antagonist istradefylline, and cariprazine failed to reverse the effort-related effects of the dopamine-depleting agent tetrabenazine. In mouse touchscreen choice tests, low doses of cariprazine also produced a low-effort bias, shifting behavior away from panel pressing. These results demonstrate that with these rodent models of avolition, cariprazine appears to act like a D2-family antagonist even at very low doses. Furthermore, the pharmacological regulation of avolition may differ from that of other negative symptoms.

Chronic Semaglutide Treatment in Rats Leads to Daily Excessive Concentration-Dependent Sucrose Intake.

The glucagon-like peptide-1 receptor (GLP-1R) agonist semaglutide (SEMA) produces 15% weight loss when chronically administered to humans with obesity. In 2 separate experiments, rats received daily injections of either vehicle (VEH) or SEMA starting at 7 µg/kg body weight (BW) and increasing over 10 days to the maintenance dose (70 µg/kg-BW), emulating clinical dose escalation strategies. During dose escalation and maintenance, SEMA rats reduced chow intake and bodyweight. Experiment 2 meal pattern analysis revealed that meal size, not number, mediated these SEMA-induced changes in chow intake. This suggests SEMA affects neural processes controlling meal termination and not meal initiation. Two-bottle preference tests (vs water) began after 10 to 16 days of maintenance dosing. Rats received either an ascending sucrose concentration series (0.03-1.0 M) and 1 fat solution (Experiment 1) or a 4% and 24% sucrose solution in a crossover design (Experiment 2). At lower sucrose concentrations, SEMA-treated rats in both experiments drank sometimes >2× the volume consumed by VEH controls; at higher sucrose concentrations (and 10% fat), intake was similar between treatment groups. Energy intake of SEMA rats became similar to VEH rats. This was unexpected because GLP-1R agonism is thought to decrease the reward and/or increase the satiating potency of palatable foods. Despite sucrose-driven increases in both groups, a significant bodyweight difference between SEMA- and VEH-treated rats remained. The basis of the SEMA-induced overconsumption of sucrose at lower concentrations relative to VEH controls remains unclear, but the effects of chronic SEMA treatment on energy intake and BW appear to depend on the caloric sources available.

The administration of Exendin-4 and CCK affects food intake differentially in female and male rats tested on an alternate day fasting paradigm

Alternate day fasting (ADF) which involves the repetition of a 2-day cycle of a day of free access to food followed by a day of limited or no access to food, is an effective dietary intervention for weight loss in both humans and rats. We have previously reported that when presented with a high energy (HE) and standard chow diet, rats maintained on an ADF schedule displayed decreased HE diet preference compared to controls. Both male and female ADF rats increased overall intake of chow. However, this increase was driven by both meal size and meal number for males and only number of meals for females. Administration of cholecystokinin (CCK) or the glucagon-like peptide 1 (GLP-1) receptor agonist Exendin-4 (Ex-4) reduces food intake. It appears that CCK decreases food intake primarily through satiety signals whereas GLP-1 signaling may reduce intake by satiety and reward cues. Here, female and male rats were administered (i.p.) saline, 3.0 µg/kg Ex-4 (3 h before test), 3.0 µg/kg CCK (15 min before test) or a combination of both. Next, all rats were presented 23-h access to both HE diet and chow following food-restriction (ADF) or free access to chow (CON). Compared to saline-control sessions, administration of the combination of Ex-4 and CCK, but not Ex-4 or CCK alone, resulted in a decrease in both HE and chow intake early in the session for male ADF rats but the combination primarily decreased chow diet intake early in the session for female ADF rats. Thus, it appears that under these energy homeostatic conditions, administration of Ex-4 or CCK alone does not affect intake in ADF rats, but the combination produces decreases in feeding that are more than the sum of their individual effects. These findings support a role for the combination of GLP-1 and CCK signaling in the changes in diet preference induced by an alternate day fasting paradigm differentially in female and male rats.

Hindbrain ghrelin and liver-expressed antimicrobial peptide 2, ligands for growth hormone secretagogue receptor, bidirectionally control food intake.

Hindbrain growth hormone secretagogue receptor (GHSR) agonism increases food intake, yet the underlying neural mechanisms remain unclear. The functional effects of hindbrain GHSR antagonism by its endogenous antagonist liver-expressed antimicrobial peptide 2 (LEAP2) are also yet unexplored. To test the hypothesis that hindbrain GHSR agonism attenuates the food intake inhibitory effect of gastrointestinal (GI) satiation signals, ghrelin (at a feeding subthreshold dose) was administered to the fourth ventricle (4V) or directly to the nucleus tractus solitarius (NTS) before systemic delivery of the GI satiation signal cholecystokinin (CCK). Also examined, was whether hindbrain GHSR agonism attenuated CCK-induced NTS neural activation (c-Fos immunofluorescence). To investigate an alternate hypothesis that hindbrain GHSR agonism enhances feeding motivation and food seeking, intake stimulatory ghrelin doses were administered to the 4V and fixed ratio 5 (FR-5), progressive ratio (PR), and operant reinstatement paradigms for palatable food responding were evaluated. Also assessed were 4V LEAP2 delivery on food intake and body weight (BW) and on ghrelin-stimulated feeding. Both 4V and NTS ghrelin blocked the intake inhibitory effect of CCK and 4V ghrelin blocked CCK-induced NTS neural activation. Although 4V ghrelin increased low-demand FR-5 responding, it did not increase high-demand PR or reinstatement of operant responding. Fourth ventricle LEAP2 reduced chow intake and BW and blocked hindbrain ghrelin-stimulated feeding. Data support a role for hindbrain GHSR in bidirectional control of food intake through mechanisms that include interacting with the NTS neural processing of GI satiation signals but not food motivation and food seeking.

Sugar Beverage Habitation Relieves Chronic Stress-Induced Anxiety-like Behavior but Elicits Compulsive Eating Phenotype via vLSGAD2 Neurons.

Chronically stressed individuals are reported to overconsume tasty, palatable foods like sucrose to blunt the psychological and physiological impacts of stress. Negative consequences of high-sugar intake on feeding behavior include increased metabolic disease burdens like obesity. However, the neural basis underlying long-term high-sugar intake-induced overeating during stress is not fully understood. To investigate this question, we used the two-bottle sucrose choice paradigm in mice exposed to chronic unpredictable mild stressors (CUMS) that mimic those of daily life stressors. After 21 days of CUMS paralleled by consecutive sucrose drinking, we explored anxiety-like behavior using the elevated plus maze and open field tests. The normal water-drinking stressed mice displayed more anxiety than the sucrose-drinking stressed mice. Although sucrose-drinking displayed anxiolytic effects, the sucrose-drinking mice exhibited binge eating (chow) and a compulsive eating phenotype. The sucrose-drinking mice also showed a significant body-weight gain compared to the water-drinking control mice during stress. We further found that c-Fos expression was significantly increased in the ventral part of the lateral septum (vLS) of the sucrose-treated stressed mice after compulsive eating. Pharmacogenetic activation of the vLS glutamate decarboxylase 2(GAD2) neurons maintained plain chow intake but induced a compulsive eating phenotype in the naïve GAD2-Cre mice when mice feeding was challenged by flash stimulus, mimicking the negative consequences of excessive sucrose drinking during chronic stress. Further, pharmacogenetic activation of the vLSGAD2 neurons aggravated anxiety of the stressed GAD2-Cre mice but did not alter the basal anxiety level of the naïve ones. These findings indicate the GABAergic neurons within the vLS may be a potential intervention target for anxiety comorbid eating disorders during stress.

A Cre-driver rat model for anatomical and functional analysis of glucagon (Gcg)-expressing cells in the brain and periphery

ObjectiveThe glucagon gene (Gcg) encodes preproglucagon, which is cleaved to form glucagon-like peptide 1 (GLP1) and other mature signaling molecules implicated in metabolic functions. To date there are no transgenic rat models available for precise manipulation of GLP1-expressing cells in the brain and periphery. MethodsTo visualize and manipulate Gcg-expressing cells in rats, CRISPR/Cas9 was used to express iCre under control of the Gcg promoter. Gcg-Cre rats were bred with tdTomato reporter rats to tag Gcg-expressing cells. Cre-dependent AAVs and RNAscope in situ hybridization were used to evaluate the specificity of iCre expression by GLP1 neurons in the caudal nucleus of the solitary tract (cNTS) and intermediate reticular nucleus (IRt), and by intestinal and pancreatic secretory cells. Food intake was assessed in heterozygous (Het) Gcg-Cre rats after chemogenetic stimulation of cNTS GLP1 neurons expressing an excitatory DREADD. ResultsWhile genotype has minimal effect on body weight or composition in chow-fed Gcg-Cre rats, homozygous (Homo) rats have lower plasma glucose levels. In neonatal and adult Gcg-Cre/tdTom rats, reporter-labeled cells are present in the cNTS and IRt, and in additional brain regions (e.g., basolateral amygdala, piriform cortex) that lack detectable Gcg mRNA in adults but display transient developmental or persistently low Gcg expression. Compared to wildtype (WT) rats, hindbrain Gcg mRNA and GLP1 protein in brain and plasma are markedly reduced in Homo Gcg-Cre rats. Chemogenetic stimulation of cNTS GLP1 neurons reduced overnight chow intake in males but not females, the effect in males was blocked by antagonism of central GLP1 receptors, and hypophagia was enhanced when combined with a subthreshold dose of cholecystokinin-8 to stimulate gastrointestinal vagal afferents. ConclusionsGcg-Cre rats are a novel and valuable experimental tool for analyzing the development, anatomy, and function of Gcg-expressing cells in the brain and periphery. In addition, Homo Gcg-Cre rats are a unique model for assessing the role of Gcg-encoded proteins in glucose homeostasis and energy metabolism.

Fibroblast growth factor 21 and dietary macronutrient intake in female mice

Fibroblast growth factor- 21 (FGF21) is a metabolic stress hormone that is released from the liver in response to various nutritional challenges. Because of its notable effects to improve metabolic health, including body fat loss, glucose control, and hepatosteatosis, several pharmaceutical analogs of FGF21 are in development for the treatment of metabolic disease. In addition, a small but developing literature clearly demonstrates that FGF21 also controls feeding behavior. Pharmacological administration of FGF21 reduces the consumption of simple sugars and other sweet tastants, and it increases the consumption of dietary proteins in males, suggesting another potential mechanism by which FGF21-treatment could improve metabolic health— by promoting healthy eating. Despite that sex is a key biological variable influencing feeding behavior and macronutrient selection, the current literature to date primarily on males. In this study, we investigated the effect of FGF21 on sucrose intake and macronutrient selection in female mice. Similar to our previous findings in male mice, we report that FGF21 administration decreases the consumption of sucrose solution by females, and that this is offset by increased chow intake. Also in agreement with our previous findings in males, we report that FGF21 increases the consumption of dietary protein by female mice, and this is offset by either reduced carbohydrate or by reduced fat intake. Lastly, we find that the effect of FGF21 to direct macronutrient intake in females depends on its actions in neurons. Overall, our data support a role for FGF21 to direct macronutrient intake in a similar manner in female and male mice.

Tirzepatide suppresses palatable food intake by selectively reducing preference for fat in rodents.

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. 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. 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. 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.

The alpha-7 nicotinic acetylcholine receptor agonist GTS-21 does not affect food intake in rats

Obesity is a prevalent disease, but effective treatments remain limited. Agonists of the alpha-7 nicotinic acetylcholine receptor (α7nAChR) promote negative energy balance in mice, but these effects are not well-studied in rats. We tested the hypothesis that the α7nAChR agonist GTS-21 would decrease food intake and body weight in adult male Sprague Dawley rats. Contrary to our hypothesis, acute systemic administration of GTS-21 produced no significant effects on chow or high-fat diet (HFD) intake. Acute intracerebroventricular (ICV) GTS-21 also had no impact on chow intake, and actually increased body weight at the highest dose tested. Previous studies suggest that GTS-21 engages the food intake-suppressive glucagon-like peptide-1 (GLP-1) system in mice. As there are known species differences in GLP-1 physiology between mice and rats, we tested the ability of GTS-21 to elicit GLP-1 secretion in rats. Our results showed that plasma levels of total GLP-1 in rats were not significantly altered by peripheral GTS-21 injection. These results represent an advance in understanding how α7nAChR activation impacts energy balance control in rodents and suggest that there may be important differences between rats and mice in the ability of GTS-21/α7nAChR activation to increase secretion of GLP-1.

Leptin receptor-expressing cells in the ventromedial nucleus of the hypothalamus contribute to enhanced CCK-induced satiety following central leptin injection.

Others have shown that leptin and cholecystokinin (CCK) act synergistically to suppress food intake. Experiments described here tested whether leptin in the ventromedial hypothalamus (VMH) contributes to the synergy with peripheral CCK in male Sprague Dawley rats. A subthreshold injection of 50-ng leptin into the VMH 1 h before a peripheral injection of 1 µg/kg CCK did not change the response to CCK in rats offered chow or low-fat purified diet, but did exaggerate the reduction in intake of high-fat diet 30 min and 1 h after injection in rats that had been food deprived for 8 h. By contrast, deletion of leptin receptor-expressing cells in the VMH using leptin-conjugated saporin (Lep-Sap) abolished the response to peripheral CCK in chow-fed rats. Lateral ventricle injection of 2-µg leptin combined with peripheral CCK exaggerated the inhibition of chow intake for up to 6 h in control rats treated with Blank-saporin, but not in Lep-Sap rats. Blank-Saporin rats offered low- or high-fat purified diet also demonstrated a dose-response inhibition of intake that reached significance with 1 µg/kg of CCK for both diets. CCK did not inhibit intake of Lep-Sap rats in either low- or high-fat-fed rats. Thus, although basal activation of VMH leptin receptors makes a significant contribution to the synergy with CCK, increased leptin activity in the VMH does not exaggerate the response to CCK in intact rats offered low-fat diets, but does enhance the response in those offered high-fat diet.NEW & NOTEWORTHY Leptin is a feedback signal in the control of energy balance, whereas cholecystokinin (CCK) is a short-term satiety signal that inhibits meal size. The two hormones synergize to promote satiety. We tested whether leptin receptors in the ventromedial nucleus of the hypothalamus (VMH) contribute to the synergy. The results suggest that there is a requirement for a baseline level of activation of leptin receptors in the VMH in order for CCK to promote satiety.