Metformin is the most prescribed drug for DM2, but its site and mechanism of action are still not well established. Here, we investigated the effects of metformin on basolateral intestinal glucose ...uptake (BIGU), and its consequences on hepatic glucose production (HGP). In diabetic patients and mice, the primary site of metformin action was the gut, increasing BIGU, evaluated through PET-CT. In mice and CaCo2 cells, this increase in BIGU resulted from an increase in GLUT1 and GLUT2, secondary to ATF4 and AMPK. In hyperglycemia, metformin increased the lactate (reducing pH and bicarbonate in portal vein) and acetate production in the gut, modulating liver pyruvate carboxylase, MPC1/2, and FBP1, establishing a gut-liver crosstalk that reduces HGP. In normoglycemia, metformin-induced increases in BIGU is accompanied by hypoglycemia in the portal vein, generating a counter-regulatory mechanism that avoids reductions or even increases HGP. In summary, metformin increases BIGU and through gut-liver crosstalk influences HGP.
Obesity and type 2 diabetes are characterized by subclinical inflammatory process. Changes in composition or modulation of the gut microbiota may play an important role in the obesity-associated ...inflammatory process. In the current study, we evaluated the effects of probiotics (Lactobacillus rhamnosus, L. acidophilus and Bifidobacterium bifidumi) on gut microbiota, changes in permeability, and insulin sensitivity and signaling in high-fat diet and control animals. More importantly, we investigated the effects of these gut modulations on hypothalamic control of food intake, and insulin and leptin signaling. Swiss mice were submitted to a high-fat diet (HFD) with probiotics or pair-feeding for 5 weeks. Metagenome analyses were performed on DNA samples from mouse feces. Blood was drawn to determine levels of glucose, insulin, LPS, cytokines and GLP-1. Liver, muscle, ileum and hypothalamus tissue proteins were analyzed by Western blotting and real-time polymerase chain reaction. In addition, liver and adipose tissues were analyzed using histology and immunohistochemistry. The HFD induced huge alterations in gut microbiota accompanied by increased intestinal permeability, LPS translocation and systemic low-grade inflammation, resulting in decreased glucose tolerance and hyperphagic behavior. All these obesity-related features were reversed by changes in the gut microbiota profile induced by probiotics. Probiotics also induced an improvement in hypothalamic insulin and leptin resistance. Our data demonstrate that the intestinal microbiome is a key modulator of inflammatory and metabolic pathways in both peripheral and central tissues. These findings shed light on probiotics as an important tool to prevent and treat patients with obesity and insulin resistance.
Adenoid cystic carcinoma (ACC) is a tumor of the salivary glands, characterized by insidious growth, recurrences, and distant metastases.
This study aimed to describe the findings of PET/CT images ...performed with 18 F-FDG (FDG PET/CT) and 18 F-PSMA-1007 (PSMA PET/CT) in patients with relapsed ACC to verify whether any of these studies are more suitable for identifying local recurrence and distant metastases.
Patients were submitted to restaging PET/CT studies with 18 F-FDG and 18 F- PSMA-1007 with a 24-hour interval between exams before treatment. Two nuclear medicine physicians compared imaging findings.
Patient 1. P.A.C., a 29-year-old female, was diagnosed with ACC of the parotid in 2016. She underwent total parotidectomy and RT. In 2021, a chest computed tomography (CT) identified lung nodules, and the patient underwent resection of the largest lesions. In 2024, the patient was submitted to restaging images with FDG PET/CT that were negative for metastases, but PSMA PET/CT images identified mild PSMA uptake in two pulmonary nodules (0.8 cm, SUV = 2.2; 0.9 cm, SUV = 3.4) suspicious for ACC metastases. The patient remains asymptomatic under supervised follow-up. Patient 2. L.C.O., a 49-year-old male with newly diagnosed ACC in the salivary gland, underwent tumor resection and RT in 2010. The patient recurred in lungs and skull and was submitted to resection of the lung nodules and total skull radiotherapy (RT). In 2022, the patient underwent RT to a metastasis in the 5th lumbar vertebrae. In 2023, FDG PET/CT revealed hypermetabolism in multiple pulmonary nodules (the largest measuring 1.8 cm, SUV = 13.4) and in the L5 vertebrae (SUV = 8.5), consistent with metastases. The PSMA PET/CT showed only mild PSMA uptake in the pulmonary nodules (the largest nodule had a SUV = 4.7) and similar PSMA uptake (as FDG) in L5 vertebrae (SUV = 8.7). The patient is currently asymptomatic. Patient 3. P.C.S., a 46- year-old male, was diagnosed with ACC in the parapharyngeal space and underwent surgical resection followed by RT in 2008. In 2022, a chest CT identified lung metastases, the largest nodule with 3.8 cm. In 2023, a FDG PET/CT demonstrated hypermetabolic lung nodule metastases (the largest measuring 3.0 and 3.8 cm; SUV = 12.3 and SUV = 6.1, respectively). The FDG PET/CT also demonstrated multiple liver nodules (the largest measuring 2.7 cm) without FDG uptake, suspicious for metastases. A PSMA PET/CT showed PSMA uptake in the same lung nodules, however incongruent when compared to FDG uptake: the two nodules measuring 3.0 and 3.8 cm had SUVs of 5.2 and 8.8, respectively). The patient currently reports dyspnea during moderate-intensity physical activity.
The data show heterogeneity in FDG PET/CT and PSMA PET/CT findings in relapsed ACC. Combining both PET/CT radiotracers can provide additional information for monitoring patients. PSMA PET/CT has the advantage of the possibility of a theranostic approach.
The study was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Apoio ao Ensino e à Pesquisa do Estado de São Paulo (Cancer Theranostics Innovation Center, CEPID FAPESP #2021/10265-8), and International Atomic Energy Agency (IAEA) technical cooperation projects for development of Latin American Countries (IAEA/TCLAC: EX-BRA6033-2401375).
Recently, the tracer Prostate Specific Membrane Antigen (PSMA), which can be labeled with the radioisotopes 68Ga or 18F, has been commercially introduced. Theoretically, as the name suggests, it is a ...substance specific to the membrane of prostate cells and prostate cancer. However, several studies have shown that it is also a marker of neoangiogenesis, leading to its uptake in various other neoplasms and benign diseases.
This study aims to evaluate the utility of radiolabeled PSMA in detecting desmoid tumors, comparing it to 18F-luorodeoxyglucose (FDG).
Three participants with a confirmed diagnosis of desmoid tumor underwent PET/CT examinations with 18F-PSMA and 18F-FDG, with a maximum interval of 3 days between examinations. Images were visually compared lesion by lesion and the maximum standardized uptake value (SUV) was calculated for each lesion and each radiopharmaceutical.
All lesions presented uptake of both 68Ga-PSMA and 18F-FDG. In the first patient, 3 lesions were identified: a mass adjacent to the pancreas measuring 5.4 cm (FDG: SUV = 2.0) (PSMA: SUV = 8.2), a mass in the right iliac fossa measuring 7.7 cm (FDG: SUV = 3.8) (PSMA: SUV = 5.7), and another involving the duodenojejunal transition measuring 4.1 cm (FDG: SUV = 1.9) (PSMA: SUV = 3.7). In the second patient, a mass was identified adjacent to the head and uncinate process of the pancreas measuring 9.2 cm (FDG: SUV = 9.8) (PSMA: SUV = 6.1). In the third patient, an irregular retroperitoneal mass was identified at the level of the aortic bifurcation (FDG: SUV = 2.3) (PSMA: SUV = 2.4).
Desmoid tumors can demonstrate uptake of both 68Ga-PSMA and 18F-FDG. The intensity of tracer uptake in the lesions is variable, with some showing greater uptake of FDG, others of PSMA, suggesting a potential complementary role for these radiotracers in desmoid tumors.
Lung cancer remains a major global cause of mortality. While 18F-FDG PET/CT is widely utilized for detection, staging, and monitoring, detecting increased glucose metabolism in tumor cells, it lacks ...theranostic potential. The prostate-specific membrane antigen (PSMA) tracer, initially linked to prostate cancer, is also recognized as a marker of neoangiogenesis, accumulating in various neoplasms and showing promising theranostic capabilities.
This study aims to compare the uptake patterns of 18F-FDG and 18F-PSMA in primary and metastatic lesions of non-small cell lung cancer.
Four male patients diagnosed with non-small cell lung cancer (including two adenocarcinomas, one squamous cell carcinoma, and one unspecified type), aged between 58 and 71 years, underwent PET/CT imaging. 18F-FDG PET/CT scans were performed 60 minutes after intravenous administration of 0.1 mCi/kg of 18F-FDG, while 18F-PSMA PET/CT scans were obtained 90 minutes after intravenous injection of 0.1 mCi/kg of 18F-PSMA. Imaging data were analyzed by two nuclear medicine physicians and one radiologist. The maximum standardized uptake value (SUVmax) of each lesion was measured for both radiotracers in the primary tumor, lymph nodes, and metastatic sites identified through visual analysis, considering values obtained above the cardiac blood pool measured in the left atrium.
A total of 100 lesions were detected, with 82 identified using 18F-FDG and 92 using 18F-PSMA. Eight lesions were exclusively detected by 18F-FDG, while 14 were only identified by 18F-PSMA. The median SUVmax of lesions in 18F-FDG and 18F-PSMA images was 5.3 (1.7 – 25.0) and 3.7 (0.7 - 12.4), respectively. Brain lesions were more readily identified on 18F-PSMA images, whereas liver lesions were more notable on 18F-FDG images due to the intense physiological uptake of 18F-FDG and 18F-PSMA in the brain and liver, respectively.
Both 18F-FDG-PET/CT and 18F-PSMA-PET/CT have the ability to identify most lesions of non-small cell lung cancer. Although 18F-PSMA images detected a greater number of lesions, the uptake intensity is generally higher with 18F-FDG. These findings suggest that the two radiopharmaceuticals may have complementary roles in lung cancer by independently detecting lesions with higher glycolytic activity or greater neoangiogenesis, or both simultaneously, which could contribute to a more personalized approach in managing these patients. The results also suggest a possible theranostic approach in selected patients with high uptake of PSMA. Further investigations involving a larger patient cohort are essential to validate these findings.
Insulin resistance in diet-induced obesity (DIO) is associated with a chronic systemic low-grade inflammation, and Toll-like receptor 4 (TLR4) plays an important role in the link among insulin ...resistance, inflammation, and obesity. The current study aimed to analyze the effect of exercise on TLR4 expression and activation in obese rats and its consequences on insulin sensitivity and signaling.
The effect of chronic and acute exercise was investigated on insulin sensitivity, insulin signaling, TLR4 activation, c-Jun NH(2)-terminal kinase (JNK) and IκB kinase (IKKβ) activity, and lipopolysaccharide (LPS) serum levels in tissues of DIO rats.
The results showed that chronic exercise reduced TLR4 mRNA and protein expression in liver, muscle, and adipose tissue. However, both acute and chronic exercise blunted TLR4 signaling in these tissues, including a reduction in JNK and IKKβ phosphorylation and IRS-1 serine 307 phosphorylation, and, in parallel, improved insulin-induced IR, IRS-1 tyrosine phosphorylation, and Akt serine phosphorylation, and reduced LPS serum levels.
Our results show that physical exercise in DIO rats, both acute and chronic, induces an important suppression in the TLR4 signaling pathway in the liver, muscle, and adipose tissue, reduces LPS serum levels, and improves insulin signaling and sensitivity. These data provide considerable progress in our understanding of the molecular events that link physical exercise to an improvement in inflammation and insulin resistance.
Introduction
Cdc2-like kinase (CLK2) is a member of CLK kinases expressed in hypothalamic neurons and is activated in response to refeeding, leptin, or insulin. Diet-induced obesity and leptin ...receptor-deficient
db/db
mice lack CLK2 signal in the hypothalamic neurons. The neurotransmiter gamma-aminobutyric acid (GABA) is among the most prevalent in the central nervous system (CNS), particularly in the hypothalamus. Given the abundance of GABA-expressing neurons and their potential influence on regulating energy and behavioral homeostasis, we aimed to explore whether the deletion of CLK2 in GABAergic neurons alters energy homeostasis and behavioral and cognitive functions in both genders of mice lacking CLK2 in Vgat-expressing neurons (Vgat-Cre; Clk2
loxP/loxP
) on chow diet.
Methods
We generated mice lacking Clk2 in Vgat-expressing neurons (Vgat-Cre; Clk2
loxP/loxP
) by mating Clk2
loxP/loxP
mice with Vgat-IRES-Cre transgenic mice and employed behavior, and physiological tests, and molecular approaches to investigate energy metabolism and behavior phenotype of both genders.
Results and discussion
We showed that deletion of CLK2 in GABAergic neurons increased adiposity and food intake in females. The mechanisms behind these effects were likely due, at least in part, to hypothalamic insulin resistance and upregulation of hypothalamic Npy and Agrp expression. Besides normal insulin and pyruvate sensitivity, Vgat-Cre; Clk2
loxP/loxP
females were glucose intolerant. Male Vgat-Cre; Clk2
loxP/loxP
mice showed an increased energy expenditure (EE). Risen EE may account for avoiding weight and fat mass gain in male Vgat-Cre; Clk2
loxP/loxP
mice. Vgat-Cre; Clk2
loxP/loxP
mice had no alteration in cognition or memory functions in both genders. Interestingly, deleting CLK2 in GABAergic neurons changed anxiety-like behavior only in females, not males. These findings suggest that CLK2 in GABAergic neurons is critical in regulating energy balance and anxiety-like behavior in a gender-specific fashion and could be a molecular therapeutic target for combating obesity associated with psychological disorders in females.
Scope
Nutritional supplementation of the maternal diet can modify the cancer susceptibility in adult offspring. Therefore, the authors evaluate the effects of a fish‐oil diet administered to a ...long‐term, during pre‐mating, gestation, and lactation, in reducing cancer‐cachexia damages in adult Walker‐256 tumor‐bearing offspring.
Methods and Results
Female rats receive control or fish oil diet during pre‐mating, gestation, and lactation. After weaning, male offspring are fed the control diet until adulthood and distributed in (C) control adult‐offspring; (W) adult tumor‐bearing offspring; (OC) adult‐offspring of maternal fish oil diet; (WOC) adult tumor‐bearing offspring of maternal fish oil diet groups. Fat body mass is preserved, muscle expression of mechanistic target of rapamicin (mTOR) and eukariotic binding protein of eukariotic factor 4E (4E‐BP1) is modified, being associated with lower 20S proteasome protein expression, and the liver alanine aminotransferase (ALT) enzyme content maintained in the WOC group. Also, the OC group shows reduced triglyceridemia.
Conclusion
In this experimental model of cachexia, the long‐term maternal supplementation is a positive strategy to improve liver function and lipid metabolism, as well as to modify muscle proteins expression in the mTOR pathway and also reduce the 20S muscle proteasome protein, without altering the tumor development and muscle wasting in adult tumor‐bearing offspring.
This study shows that maternal supplementation with fish oil diet during the pre‐mating, gestation, and lactation phases could influence some adult tumor‐bearing offspring's responses. The long‐term fish oil supplementation preserved the offspring body fat mass and modulated the lipid metabolism and hepatic function, showing that these tumor‐induced damages were minimized. In addition, some skeletal muscle proteins related to proteasome subunits were also modified and required more studies in this way.
Hypothalamic inflammation is a common feature of experimental obesity. Dietary fats are important triggers of this process, inducing the activation of toll-like receptor-4 (TLR4) signaling and ...endoplasmic reticulum stress. Microglia cells, which are the cellular components of the innate immune system in the brain, are expected to play a role in the early activation of diet-induced hypothalamic inflammation. Here, we use bone marrow transplants to generate mice chimeras that express a functional TLR4 in the entire body except in bone marrow-derived cells or only in bone marrow-derived cells. We show that a functional TLR4 in bone marrow-derived cells is required for the complete expression of the diet-induced obese phenotype and for the perpetuation of inflammation in the hypothalamus. In an obesity-prone mouse strain, the chemokine CX3CL1 (fractalkine) is rapidly induced in the neurons of the hypothalamus after the introduction of a high-fat diet. The inhibition of hypothalamic fractalkine reduces diet-induced hypothalamic inflammation and the recruitment of bone marrow-derived monocytic cells to the hypothalamus; in addition, this inhibition reduces obesity and protects against diet-induced glucose intolerance. Thus, fractalkine is an important player in the early induction of diet-induced hypothalamic inflammation, and its inhibition impairs the induction of the obese and glucose intolerance phenotypes.
Swiss mice belong to an outbred strain of mice largely used as a model for experimental obesity induced by high fat diet (HFD). We have previously demonstrated that a given cohort of age-matched ...Swiss mice is hallmarked by heterogeneous changes in body weight when exposed to HFD. The reasons underlying such variability, however, are not completely understood. Therefore we aimed to clarify the mechanisms underlying the variability in spontaneous weight gain in age-matched male swiss mice. To achieve that, individuals in a cohort of age-matched male Swiss mice were categorized as prone to body mass gain (PBMG) and resistant to body mass gain (RBMG). PBMG animals had higher caloric intake and body mass gain. RBMG and PBMG mice had a similar reduction in food intake when challenged with leptin but only RBMG exhibited a drop in ghrelin concentrations after refeeding. PBMG also showed increased midbrain levels of ghrelin receptor (Ghsr) and Dopamine receptor d2 (Drd2) mRNAs upon refeeding. Pharmacological blockade of GHSR with JMV3002 failed to reduce food intake in PMBG mice as it did in RBMG. On the other hand, the response to JMV3002 seen in PBMG was hallmarked by singular transcriptional response in the midbrain characterized by a simultaneous increase in both tyrosine hydroxylase (Th) and Proopiomelanocortin (Pomc) expressions. In conclusion, our data show that differences in the expression of genes related to the reward system in the midbrain as well as in ghrelin concentrations in serum correlate with spontaneous variability in body mass and food intake seen in age-matched male Swiss mice.
•Age-matched Swiss mice are either prone or resistant to body weight gain.•Mice prone to body weight gain display increased spontaneous food intake.•Mice prone to body weight gain have increased midbrain expression of Ghsr and Drd2.•Mice resistant to body weight gain exhibit a drop in ghrelin levels after refeeding.•GHSR blockade fails to inhibit food intake in mice prone to body weight gain.
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