Diet-induced Obese Male Mice Research Articles

The Chimeric Peptide (GEP44) Reduces Body Weight, Energy Intake, and Energy Expenditure in Diet-Induced Obese Rats.

We recently reported that a chimeric peptide (GEP44) targeting the glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y1- and Y2-receptors decreased body weight (BW), energy intake and core temperature in diet-induced obese (DIO) male and female mice. Given that GEP44 was found to reduce core temperature (surrogate measure of energy expenditure (EE)) in DIO mice, we hypothesized that GEP44 would reduce EE in male and female high fat diet (HFD)-fed rats. To test this, rats were maintained on a HFD for at least 4 months to elicit DIO prior to undergoing a sequential 2-day vehicle period, 2-day GEP44 (50 nmol/kg) period and a minimum 2-day washout period and detailed measures of energy homeostasis. GEP44 (50 nmol/kg) reduced EE (indirect calorimetry), respiratory exchange ratio (RER), core temperature, activity, energy intake and BW in male and female rats. As in our previous study in mice, GEP44 reduced BW in male and female HFD-fed rats by 3.8 ± 0.2% and 2.3 ± 0.4%, respectively. These effects appear to be mediated by increased lipid oxidation and reductions of energy intake as GEP44 reduced RER and cumulative energy intake in male and female HFD-fed rats. The strong reduction of body weight in response to GEP44 is related to a robust reduction of energy intake, but not to stimulation of EE. The paradoxical finding that GEP44 reduced EE might be secondary to a reduction of diet-induced thermogenesis or might indicate an important mechanism to limit the overall efficacy of GEP44 to prevent further weight loss.

Pre-immunization of diet-induced obese male mice with inactivated pathogens increases power in a liraglutide intervention study.

Pre-immunization with inactivated antigens has been developed as an alternative to the use of 'dirty' mice, which in contrast to specific pathogen free (SPF) mice, harbour a range of pathogens. Within certain research areas, such mice are considered better models for humans than SPF mice, as they have an immune system that better mirrors human immunity. We inactivated murine adenovirus type 1 (FL), minute virus of mice, mouse hepatitis virus (A59), respirovirus muris (Sendai), Theiler's encephalomyelitis virus (GD7) and Mycoplasma pulmonis by ultraviolet irradiation. We show that pre-immunization with these inactivated pathogens combined with adjuvant prior to the dietary induction of obesity in C57BL/6NTac mice substantially reduced the group sizes needed for showing an effect of the GLP-1 receptor analogue, liraglutide. Nesting, open field and novel object behaviours of the mice were unaffected. We conclude that pre-immunization with inactivated pathogens may be a simple tool to increase power in this type of intervention study on the DIO mouse model.

ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice.

α/β-hydrolase domain 6 (ABHD6) is a lipase linked to physiological functions affecting energy metabolism. Brain ABHD6 degrades 2-arachidonoylglycerol and thereby modifies cannabinoid receptor signalling. However, its functional role within mesoaccumbens circuitry critical for motivated behaviour and considerably modulated by endocannabinoids was unknown. Using three viral approaches, we show that control of the nucleus accumbens by neuronal ABHD6 is a key determinant of body weight and reward-directed behaviour in male mice. Contrary to expected outcomes associated with increasing endocannabinoid tone, loss of ABHD6 in nucleus accumbens, but not ventral tegmental area, neurons completely prevents diet-induced obesity, reduces food- and drug-seeking and enhances physical activity without affecting anxiodepressive behaviour. These effects are explained by attenuated inhibitory synaptic transmission onto medium spiny neurons. ABHD6 deletion in nucleus accumbens neurons and dopamine ventral tegmental area neurons produces contrasting effects on effortful responding for food. Intraventricular infusions of an ABHD6 inhibitor also restrain appetite and promoteweight loss. Together, these results reveal functional specificity of pre- and post-synaptic mesoaccumbens neuronal ABHD6 to differentially control energy balance and propose ABHD6 inhibition as a potential anti-obesity tool.

Serum Extracellular Vesicles Reveal Metabolic Responses to Time-Restricted Feeding in High Fat Diet-Induced Obesity in Male Mice.

Extracellular vesicle (EV) secretion and cargo composition are dysregulated in metabolic diseases. This study aimed to identify changes in the EV size profile and protein cargoes in diet-induced obesity following time-restricted feeding (TRF) and to establish the role of EVs in obesity-related metabolic responses. Mice were fed a high-fat diet (HFD) for 18 weeks prior to being placed either ad libitum or a time-restricted feeding for an additional 10 weeks. Mice on a normal chow ad libitum served as the control. The TRF group had food available for 10 hours and fasted for 14 hours per day. The serum EV size profile and amount displayed sex- and age-dependent changes in HFD-induced obesity, with age reducing EV amounts. HFD decreased small EV populations and increased larger EV populations, while TRF reversed these changes. Quantitative proteomic analysis showed that the abundance and composition of EV proteins changed in response to both acute stimulation with lipopolysaccharides (LPS) and HFD. Gene ontology analysis identified specific sets of EV proteins and their involved biological processes, reflecting the effect of LPS and HFD, as well as the reversal effect of TRF on metabolic and inflammatory pathways. EV proteins altered by HFD and those reversed by TRF had low protein overlap but significant functional overlap in biological processes. TRF activated the PPAR signaling pathway and the AKT-mTOR signaling pathway. The most significant impacts of HFD and TRF were observed on lipoprotein and carbohydrate metabolism, complement system, and neutrophil degranulation. The reversal effect of TRF on the complement system was pathway-specific, significantly activating the lectin complement pathway and restoring neutrophil degranulation. Our data indicate that EVs are involved in diet-induced metabolic and inflammatory responses. Different EV populations may carry distinct sets of proteins involved in specific biological processes, thereby regulating diverse metabolic pathways efficiently.

Phlorizin ameliorates cognitive and behavioral impairments via the microbiota-gut-brain axis in high-fat and high-fructose diet-induced obese male mice

The long-term high-fat, high-sugar diet exacerbates type 2 diabetes mellitus (T2DM)-related cognitive impairments. Phlorizin, a well-studied natural compound found in apples and other plants, is recognized for its bioactive properties, including modulation of glucose and lipid metabolism. Despite its established role in mitigating metabolic disorders, the neuroprotective effects of phlorizin, particularly against diabetes-related cognitive dysfunction, have not been fully elucidated. Therefore, the present study aimed to investigate the effect of dietary supplementation of phlorizin on high-fat and high-fructose diet (HFFD)-induced cognitive dysfunction and evaluate the crucial role of the microbiota-gut-brain axis. We found that dietary supplementation of phlorizin for 14 weeks effectively prevented glucolipid metabolism disorder, spatial learning impairment, and memory impairment in HFFD mice. In addition, phlorizin improved the HFFD-induced decrease in synaptic plasticity, neuroinflammation, and excessive activation of microglia in the hippocampus. Transcriptomics analysis shows that the protective effect of phlorizin on cognitive impairment was associated with increased expression of neurotransmitters and synapse-related genes in the hippocampus. Phlorizin treatment alleviated colon microbiota disturbance, mainly manifested by an increase in gut microbiota diversity and the abundance of short-chain fatty acid (SCFA)-producing bacteria. The level of microbial metabolites, including SCFA, inosine 5′-monophosphate (IMP), and D (−)-beta-hydroxybutyric acid (BHB) were also significantly increased after phlorizin treatment. Integrating multiomics analysis observed tight connections between phlorizin-regulated genes, microbiota, and metabolites. Furthermore, removal of the gut microbiota via antibiotics treatment diminished the protective effect of phlorizin against HFFD-induced cognitive impairment, underscoring the critical role of the gut microbiota in mediating cognitive behavior. Importantly, supplementation with SCFA and BHB alone mimicked the regulatory effects of phlorizin on cognitive function. Therefore, phlorizin shows promise as a potential nutritional therapy for addressing cognitive impairment associated with metabolic disorders. Further research is needed to explore its effectiveness in preventing and alleviating neurodegenerative diseases.

A neuronal circuit driven by GLP-1 in the olfactory bulb regulates insulin secretion

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.

Endothelial cell HDAC1 mediates aortic stiffness in diet-induced obese mice

Histone deacetylase 1 (HDAC1) is an important regulator of cell differentiation and is associated with progression of cardiovascular disease (CVD). Our lab previously showed that over-expression of HDAC1 in cultured endothelial cells reduces NO production. Other investigators have shown increased HDAC1 protein in models of CVD. However, there is a gap in knowledge of whether endothelial-specific HDAC1 mediates vascular dysfunction in models of CVD. Diet induced obesity (DIO) is a leading risk factor for CVD, thus our studies are focused on a chronic high fat feeding mouse model. Our studies utilize a mouse model of DIO where mice are fed a normal diet (ND, 10% fat) or high fat diet (DIO, 45% fat) beginning at 8 weeks of age for 20 weeks. Previously, we showed that this model of DIO in male mice significantly increases aortic stiffness (measured by pulse wave velocity, PWV) and increases aortic thickness compared to ND (PWV: unpaired T test, n=9-12, normal diet (ND) vs DIO, p=<0.0001; Aortic Thickness: unpaired T test, n=6, ND vs DIO, p=0.005). We hypothesized that endothelial-specific HDAC1 mediates aortic dysfunction in a mouse model of DIO. We generated inducible endothelial-Scl-Cre-ER-HDAC1 knockout (KO) mice (iEC-HDAC1KO), which specifically deletes HDAC1 in endothelial cells after tamoxifen injection, and the flox control mice (iEC-HDAC1flox), which does not delete HDAC1 after tamoxifen injection. We assessed aortic stiffness of iEC-HDAC1 KO and iEC-HDAC1flox in ND and DIO mice. We treated with tamoxifen for 5 days when ND mice were 20 weeks old and measured PWV 2 weeks later. Interestingly, iEC-HDAC1KO mice had significantly reduced PWV compared to iEC-HDAC1flox mice on ND (unpaired T test; n=4-5, p=0.009). At week 18 of the DIO protocol, mice were given daily tamoxifen injections for 5 days. After week 20 of the DIO protocol, iEC-HDAC1KO DIO mice had significantly reduced PWV compared to iEC-HDAC1flox DIO mice (unpaired T test; n=4-5; p=0.008). These data indicate that endothelial-specific HDAC1 mediates vascular stiffness and remodeling in high fat fed mice. Further investigation is needed to understand the relationship of endothelial HDAC1 and NO in the context of DIO and aortic health. Funding: R01 DK134562, F31HL167626. This is the full abstract presented at the American Physiology Summit 2024 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.

ZnPP-laden nanoparticles improve glucose homeostasis and chronic inflammation during obesity.

Chronic inflammation plays a pivotal role in the development of Type 2 diabetes mellitus (T2DM). Previous studies have shown that haem oxygenase-1 (HO-1) plays a proinflammatory role during metabolic stress, suggesting that HO-1 inhibition could be an effective strategy to treat T2DM. However, the application of HO-1 inhibitors is restricted due to solubility-limited bioavailability. In this study, we encapsulated the HO-1 inhibitor, zinc protoporphyrin IX (ZnPP), within nanoparticles and investigated their role in regulating glucose homeostasis and chronic inflammation during obesity. We delivered DMSO-dissolved ZnPP (DMSO-ZnPP) and ZnPP-laden nanoparticles (Nano-ZnPP) to diet-induced obese male mice for 6weeks. Glucose and insulin tolerance tests were carried out, liver and adipose tissue gene expression profiles analysed, and systemic inflammation analysed using flow cytometry. Nanoparticles significantly increased the delivery efficiency of ZnPP in both cells and mice. In mice with diet-induced obesity, inhibition of HO-1 by Nano-ZnPP significantly decreased adiposity, increased insulin sensitivity, and improved glucose tolerance. Moreover, Nano-ZnPP treatment attenuated both local and systemic inflammatory levels during obesity. Mechanistically, Nano-ZnPP significantly attenuated glucagon, TNF, and fatty acid synthesis signalling pathways in the liver. In white adipose tissue, the oxidative phosphorylation signalling pathway was enhanced and the inflammation signalling pathway diminished by Nano-ZnPP. Our results show that Nano-ZnPP has better effects on the improvement of glucose homeostasis and attenuation of chronic inflammation, than those of DMSO-dissolved ZnPP. These findings indicate that ZnPP-laden nanoparticles are potential therapeutic agents for treating T2DM.

Enhanced Metabolic Effects of Fish Oil When Combined with Vitamin D in Diet-Induced Obese Male Mice.

Vitamin D (vit D) and fish oil (FO) both offer unique health benefits, however, their combined effects have not been evaluated in obesity and nonalcoholic fatty liver disease (NAFLD). Hence, we hypothesized that vit D and FO supplementation would have additive effects in reducing obesity-associated inflammation and NAFLD. Male C57BL6 mice were split into four groups and fed a high fat (HF) diet supplemented with a low (HF; +200 IU vit D) or high dose of vitamin D (HF + D; +1000 IU vit D); combination of vit D and FO (HF-FO; +1000 IU vit D); or only FO (HF-FO; +200 IU vit D) for 12 weeks. We measured body weight, food intake, glucose tolerance, and harvested epididymal fat pad and liver for gene expression analyses. Adiposity was reduced in groups supplemented with both FO and vit D. Glucose clearance was higher in FO-supplemented groups compared to mice fed HF. In adipose tissue, markers of fatty acid synthesis and oxidation were comparable in groups that received vit D and FO individually in comparison to HF. However, the vit D and FO group had significantly lower fatty acid synthesis and higher oxidation compared to the other groups. Vit D and FO also significantly improved fatty acid oxidation, despite similar fatty acid synthesis among the four groups in liver. Even though we did not find additive effects of vit D and FO, our data provide evidence that FO reduces markers of obesity in the presence of adequate levels of vit D.

Global, neuronal or β cell-specific deletion of inceptor improves glucose homeostasis in male mice with diet-induced obesity.

Insulin resistance is an early complication of diet-induced obesity (DIO)1, potentially leading to hyperglycaemia and hyperinsulinaemia, accompanied by adaptive β cell hypertrophy and development of type 2 diabetes2. Insulin not only signals via the insulin receptor (INSR), but also promotes β cell survival, growth and function via the insulin-like growth factor 1 receptor (IGF1R)3-6. We recently identified the insulin inhibitory receptor (inceptor) as the key mediator of IGF1R and INSR desensitization7. But, although β cell-specific loss of inceptor improves β cell function in lean mice7, it warrants clarification whether inceptor signal inhibition also improves glycaemia under conditions of obesity. We assessed the glucometabolic effects of targeted inceptor deletion in either the brain or the pancreatic β cells under conditions of DIO in male mice. In the present study, we show that global and neuronal deletion of inceptor, as well as its adult-onset deletion in the β cells, improves glucose homeostasis by enhancing β cell health and function. Moreover, we demonstrate that inceptor-mediated improvement in glucose control does not depend on inceptor function in agouti-related protein-expressing or pro-opiomelanocortin neurons. Our data demonstrate that inceptor inhibition improves glucose homeostasis in mice with DIO, hence corroborating that inceptor is a crucial regulator of INSR and IGF1R signalling.

Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R

Overfeeding triggers homeostatic compensatory mechanisms that counteract weight gain. Here, we show that both lean and diet-induced obese (DIO) male mice exhibit a potent and prolonged inhibition of voluntary food intake following overfeeding-induced weight gain. We reveal that FGF21 is dispensable for this defense against weight gain. Targeted proteomics unveiled novel circulating factors linked to overfeeding, including the protease legumain (LGMN). Administration of recombinant LGMN lowers body weight and food intake in DIO mice. The protection against weight gain is also associated with reduced vascularization in the hypothalamus and sustained reductions in the expression of the orexigenic neuropeptide genes, Npy and Agrp, suggesting a role for hypothalamic signaling in this homeostatic recovery from overfeeding. Overfeeding of melanocortin 4 receptor (MC4R) KO mice shows that these mice can suppress voluntary food intake and counteract the enforced weight gain, although their rate of weight recovery is impaired. Collectively, these findings demonstrate that the defense against overfeeding-induced weight gain remains intact in obesity and involves mechanisms independent of both FGF21 and MC4R.

Dopamine D2 receptor antagonist counteracts hyperglycemia and insulin resistance in diet-induced obese male mice.

Obesity leads to insulin resistance (IR) and type 2 diabetes. In humans, low levels of the hormone prolactin (PRL) correlate with IR, adipose tissue (AT) dysfunction, and increased prevalence of T2D. In obese rats, PRL treatment promotes insulin sensitivity and reduces visceral AT adipocyte hypertrophy. Here, we tested whether elevating PRL levels with the prokinetic and antipsychotic drug sulpiride, an antagonist of dopamine D2 receptors, improves metabolism in high fat diet (HFD)-induced obese male mice. Sulpiride treatment (30 days) reduced hyperglycemia, IR, and the serum and pancreatic levels of triglycerides in obese mice, reduced visceral and subcutaneous AT adipocyte hypertrophy, normalized markers of visceral AT function (PRL receptor, Glut4, insulin receptor and Hif-1α), and increased glycogen stores in skeletal muscle. However, the effects of sulpiride reducing hyperglycemia were also observed in obese prolactin receptor null mice. We conclude that sulpiride reduces obesity-induced hyperglycemia by mechanisms that are independent of prolactin/prolactin receptor activity. These findings support the therapeutic potential of sulpiride against metabolic dysfunction in obesity.

Single-Cell Transcriptomics Identifies Pituitary Gland Changes in Diet-Induced Obesity in Male Mice.

Obesity is a chronic disease with increasing prevalence worldwide. Obesity leads to an increased risk of heart disease, stroke, and diabetes, as well as endocrine alterations, reproductive disorders, changes in basal metabolism, and stress hormone production, all of which are regulated by the pituitary. In this study, we performed single-cell RNA sequencing of pituitary glands from male mice fed control and high-fat diet (HFD) to determine obesity-mediated changes in pituitary cell populations and gene expression. We determined that HFD exposure is associated with dramatic changes in somatotrope and lactotrope populations, by increasing the proportion of somatotropes and decreasing the proportion of lactotropes. Fractions of other hormone-producing cell populations remained unaffected. Gene expression changes demonstrated that in HFD, somatotropes became more metabolically active, with increased expression of genes associated with cellular respiration, and downregulation of genes and pathways associated with cholesterol biosynthesis. Despite a lack of changes in gonadotrope fraction, genes important in the regulation of gonadotropin hormone production were significantly downregulated. Corticotropes and thyrotropes were the least affected in HFD, while melanotropes exhibited reduced proportion. Lastly, we determined that changes in plasticity and gene expression were associated with changes in hormone levels. Serum prolactin was decreased corresponding to reduced lactotrope fraction, while lower luteinizing hormone and follicle-stimulating hormone in the serum corresponded to a decrease in transcription and translation. Taken together, our study highlights diet-mediated changes in pituitary gland populations and gene expression that play a role in altered hormone levels in obesity.

The effects of Glycyrrhiza Glabra extract in high-fat diet-induced obese male mice: A controlled experimental study

AimsThis study sought to evaluate anti-obesity effects, improved metabolic function, and spermatogenesis of Licorice root extract at doses of 343 mg/kg and 686 mg/kg. MethodsThis was a controlled experimental, descriptive cross-sectional, longitudinal study follow-up over 10 weeks of nourishment. We generated an obesity model in white mice (Swiss albino) in 6 weeks with a high-fat diet (52–53% lipid, 610 Kcal/100g). Besides, the hydroethanolic extract of Radix Glycyrrhizae (RG) was prepared. Then, we divided mice into 4 groups (NFD, HFD, RG343, RG686) with 12 mice/group. We followed morphological indices, metabolic function, and spermatogenesis after 4 weeks of taking this extract. ResultsFollowing the intervention, mice exhibited reduced weight, weight gain, BMI, and waist circumference. However, there was no difference between the 2 doses. Moreover, blood glucose, visceral fat mass, total cholesterol, and LDL-c levels of mice after the intervention were lower. Furthermore, there was a clear difference between the two doses. After the intervention, mice had larger penis, testes, epididymis, and seminal vesicle diameters and improved semen parameters, noting the difference between the two doses. ConclusionLicorice root extract helps to reduce weight, BMI, and visceral fat and improve metabolic function and spermatogenesis of obese mice. Significantly, the dose of 686 mg/kg was more effective than the dose of 343 mg/kg.

SAT038 Dietary Trans-10,cis-12 Conjugated Linoleic Acid Regulates Glucose Levels In Mice With Severe Insulin Resistance: Potential Effects On The Liver Via HNF4α And FOX01

Abstract Disclosure: S.M. Lee: None. J.T. Muratalla: None. C.W. Liew: None. J. Cordoba-Chacon: None. Plasma trans-10 cis-12-conjugated linoleic acid CLA (t10c12-CLA) is inversely associated with increased risk of diabetes in humans. In mice, it is well-known that t10c12-CLA induces whole-body insulin resistance due to severe lipodystrophy (loss of whole-body adipose tissue). However, t10c12-CLA-fed mice show normal glucose levels and, t10c12-CLA improved glucose clearance in models with preexisting insulin resistance: Zucker fatty/diabetic rats, obese and insulin resistant Ldlr-/- mice, and diet-induced obese and insulin resistant male mice. In this study, we assessed whether supplementation of t10c12-CLA in a low-fat diet reduces glucose levels in adipocyte-specific insulin receptor knockout (IRFKO) mice, which is a mouse model of congenital lipodystrophy. In addition to lipodystrophy, IRFKO mice show liver steatosis and increased blood glucose levels that are consequences of whole-body insulin resistance and increased hepatic gluconeogenesis. Briefly, 5-6-week-old male and female control and IRFKO mice were fed with a low-fat diet supplemented with 0.8% t10c12-CLA for 5 weeks. In IRFKO mice, dietary t10c12-CLA did not reduce adipose tissue mass. However, dietary t10c12-CLA increased liver steatosis and plasma insulin levels. Surprisingly, dietary t10c12-CLA reduced glucose levels in both male and female IRFKO mice. Also, dietary t10c12-CLA reduced food intake and polydipsia, which were increased in IRFKO mice due to lipodystrophy and hyperglycemia, respectively. A transcriptomic analysis (RNA-seq) of livers of control and IRFKO male mice fed with a t10c12-CLA diet showed that t10c12-CLA reduced the expression of the key gluconeogenic and mitochondrial fatty oxidation genes. Previous studies have suggested that t10c12-CLA reduces the expression of Forkhead box 01 (Fox01) and Hepatocyte nuclear factor 4 alpha (HNF4α). Of note, the livers of t10c12-CLA-fed control and IRFKO male mice showed a downregulation of positive targets of FoxO1 and HNF4α. In addition, livers of t10c12-CLA-fed mice showed reduced total FOXO1 protein levels, and increased phosphorylation of FOXO1 in t10c12-CLA-fed IRFKO mice. These findings suggest that t10c12-CLA could be directly acting on the liver to alter HNF4α and FOXO1-dependent regulation of hepatic fatty acid oxidation and glucose production. These actions may explain why t10c12-CLA-fed mice do not show increased glucose levels and is potentially linked to the inverse association between t10c12-CLA levels and diabetes risk. Presentation: Saturday, June 17, 2023

Inhibition of SOCS3 signaling in the nucleus tractus solitarii and retrotrapezoid nucleus alleviates hypoventilation in diet-induced obese male mice

The central leptin signaling system has been found to facilitate breathing and is linked to obesity-related hypoventilation. Activation of leptin signaling in the nucleus tractus solitarii (NTS) and retrotrapezoid nucleus (RTN) enhances respiratory drive. In this study, we investigated how medullary leptin signaling contributes to hypoventilation and whether respective deletion of SOCS3 in the NTS and RTN could mitigate hypoventilation in diet-induced obesity (DIO) male mice. Our findings revealed a decrease in the number of CO2-activated NTS neurons and downregulation of acid-sensing ion channels in DIO mice compared to lean control mice. Moreover, NTS leptin signaling was disrupted, as evidenced by the downregulation of phosphorylated STAT3 and the upregulation of SOCS3 in DIO mice. Importantly, deleting SOCS3 in the NTS and RTN significantly improved the diminished hypercapnic ventilatory response in DIO mice. In conclusion, our study suggests that disrupted medullary leptin signaling contributes to obesity-related hypoventilation, and inhibiting the upregulated SOCS3 in the NTS and RTN can alleviate this condition.

A natural Nrf2 activator glucoraphanin improves hepatic steatosis in high-fat diet-induced obese male mice associated with AMPK activation.

The online version contains supplementary material available at 10.1007/s13340-023-00658-6.

Diet-Induced Obese Male Mice Treated with a Rationally Designed P450 8B1 Inhibitor for 28 Days Successfully Increased CDCA to CA Ratios but Lacked Improved Glucose Tolerance and Body Weight

Altering the bile acid composition by inhibiting cytochrome P450 8B1 enzyme (CYP8B1) activity results in a decrease in the production of cholic acid (CA, 12α-hydroxylated bile acids) while increasing chenodeoxycholic acid (CDCA). Previous studies have shown that knocking out the Cyp8b1 gene in mice protects against diet-induced obesity and improves glucose tolerance and fat deposition in the liver. The objective of this study was to test the hypothesis that the inhibition of P450 8B1 enzyme activity with a rationally designed small molecule drug would alleviate diet-induced obesity and improve metabolic health. Male C57BL/6J mice (8-10 weeks old) were fed a high-fat and high sucrose (HF) diet over 10 weeks. When mice in the HF group were obese and developed glucose intolerance, half of the mice were treated with P450 8B1 inhibitor (HF/D), and the other half were treated with vehicle (HF/V, 20% β-hydroxypropyl cycolodextrin in the PBS). Mice fed a low fat and low sucrose diet treated with vehicle were used as a reference control (LF/V). Mice in the HF/D group were treated with 100 mg/kg/day, while mice in the vehicle groups (HF/V and LF/V) were administered with the same volume of vehicle. All mice were treated at the same time each morning by oral gavage for 28 days. Bodyweight and food intake were measured weekly. Glucose (GTT)- and insulin tolerance (ITT) tests were conducted before treatment and after treatment. Stool samples were extracted to measure the amount of CDCA and CA by high-resolution mass spectrometry. We found that the HF/D group did not have altered body weight, food intake, and fat composition compared to the HF/V group for the duration of the treatment (28 days). In addition, the HF/D group did not show any improvement in GTT and ITT during the 28 days of treatment. Despite these results related to body weight, GTT, and ITT, the stool samples from the HF/D group generally had a larger ratio of CDCA to CA compared to the HF/V group (CDCA/CA ratios for HF/D vs. HF/V were: 5.5, 9.4, 2.7, 4.1, 3.3 vs. 0.5, 1.5, 2.2, 8.4), suggesting that the inhibition of P450 8B1 did occur in the HFD group. The lipid droplet in the liver also decreased in some mice treated in the HF/D group. Our results suggest that a newly designed inhibitor that has a higher affinity towards the P450 8B1 enzyme relative to our originally designed inhibitor may reduce fatty liver diseases by modifying bile acid composition more effectively. Alternatively, future studies are warranted where the HF mice will be treated for a duration longer than 28 days to check whether the CDCA/CA ratio matches the physiological alterations including body weight and glucose homeostasis. This study was supported by the National Institute of Health [NIH, NIGMS, grant GM125603] to E. Chung 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.

Loss of C3a and C5a receptors promotes adipocyte browning and attenuates diet-induced obesity via activating inosine/A2aR pathway.

Complement activation is thought to underline the pathologic progression of obesity-related metabolic disorders; however, its role in adaptive thermogenesis has scarcely been explored. Here, we identify complement C3a receptor (C3aR) and C5a receptor (C5aR) as critical switches to control adipocyte browning and energy balance in male mice. Loss of C3aR and C5aR in combination, more than individually, increases cold-induced adipocyte browning and attenuates diet-induced obesity in male mice. Mechanistically, loss of C3aR and C5aR increases regulatory Tcell (Treg) accumulation in the subcutaneous white adipose tissue during cold exposure or high-fat diet. Activated Tregs produce adenosine, which is converted to inosine by adipocyte-derived adenosine deaminases. Inosine promotes adipocyte browning in a manner dependent on activating adenosine A2a receptor. These data reveal a regulatory mechanism of complement in controlling adaptive thermogenesis and suggest that targeting the C3aR/C5aR pathways may represent a therapeutic strategy in treating obesity-related metabolic diseases.

Depot-Dependent Impact of Time-Restricted Feeding on Adipose Tissue Metabolism in High Fat Diet-Induced Obese Male Mice.

Time-restricted feeding (TRF) is known to be an effective strategy for weight loss and metabolic health. TRF's effect on metabolism is complex and likely acts on various pathways within multiple tissues. Adipose tissue plays a key role in systemic homeostasis of glucose and lipid metabolism. Adipose tissue dysregulation has been causally associated with metabolic disorders in obesity. However, it is largely unknown how TRF impacts metabolic pathways such as lipolysis, lipogenesis, and thermogenesis within different in adipose tissue depots in obesity. To determine this, we conducted a 10-week TRF regimen in male mice, previously on a long-term high fat diet (HFD) and subjected the mice to TRF of a HFD for 10 h per day or ad libitum. The TRF regimen showed reduction in weight gain. TRF restored HFD-induced impairment of adipogenesis and increased lipid storage in white adipose tissues. TRF also showed a depot-dependent effect in lipid metabolism and restored ATP-consuming futile cycle of lipogenesis and lipolysis that is impaired by HFD within epididymal adipose tissue, but not inguinal fat depot. We demonstrate that TRF may be a beneficial option as a dietary and lifestyle intervention in lowering bodyweight and improving adipose tissue metabolism.