Obesity-Associated Alterations in Glucose Metabolism Are Reversed by Chronic Bilateral Stimulation of the Abdominal Vagus Nerve

Roh E., Song D.K., Kim M.

Accumulated evidence from genetic animal models suggests that the brain, particularly the hypothalamus, has a key role in the homeostatic regulation of energy and glucose metabolism. The brain integrates multiple metabolic inputs from the periphery through nutrients, gut-derived satiety signals and adiposity-related hormones. The brain modulates various aspects of metabolism, such as food intake, energy expenditure, insulin secretion, hepatic glucose production and glucose/fatty acid metabolism in adipose tissue and skeletal muscle. Highly coordinated interactions between the brain and peripheral metabolic organs are critical for the maintenance of energy and glucose homeostasis. Defective crosstalk between the brain and peripheral organs contributes to the development of obesity and type 2 diabetes. Here we comprehensively review the above topics, discussing the main findings related to the role of the brain in the homeostatic regulation of energy and glucose metabolism. Highly coordinated interactions between the brain and other organs of the body are critical for controlling the supply of energy from food. Min-Seon Kim and colleagues at the University of Ulsan in South Korea review these interactions, particularly the role of hypothalamus, a part of brain. They focus on the processes that keep energy supply and glucose metabolism within appropriate limits. The brain monitors energy intake by sensing gut hormones released when we eat, and by detecting nutrients in the blood. The brain also receives signals reporting the amounts of fatty or “adipose” tissue in the body. In response to these and other signals the brain controls food intake and metabolism. Understanding the systems that control glucose and energy balance will help to develop new drugs to combat obesity and diabetes.

Meyers E.E., Kronemberger A., Lira V., Rahmouni K., Stauss H.M.

Parasympathetic activation reduces hepatic glucose release and increases pancreatic insulin secretion in hyperglycemic conditions. Thus, vagal nerve stimulation (VNS) may potentially be effective in treating type II diabetes. To investigate this possibility, we hypothesized that VNS reduces blood glucose concentration [Glu] via insulin secretion. [Glu] together with insulin and glucagon serum concentrations were determined in anesthetized rats during baseline conditions and 120 min of cervical VNS with the nerve left intact for combined afferent and efferent VNS (n = 9) or the nerve sectioned proximal or distal from the stimulation electrode for selective efferent (n = 8) or afferent (n = 7) VNS, respectively. Afferent VNS caused a strong and sustained increase in [Glu] (+108.9 ± 20.9% or +77.6 ± 15.4%, after 120 min of combined afferent and efferent VNS or selective afferent VNS) that was not accompanied by an increase in serum insulin concentration. However, serum insulin levels increased significantly with selective efferent VNS (+71.2 ± 27.0% after 120 min of VNS) that increased [Glu] only temporarily (+28.8 ± 11.7% at 30 min of VNS). Efferent VNS initially increased serum glucagon concentration which remained elevated for 120 min when efferent VNS was combined with afferent VNS, but returned to baseline with selective efferent VNS. These findings demonstrate that afferent VNS causes a marked and sustained increase in [Glu] that is partly mediated by suppression of pancreatic insulin secretion. In contrast, efferent VNS stimulates pancreatic glucagon secretion that appears to be antagonized by insulin secretion in the case of selective efferent VNS. Selective efferent VNS may potentially be effective in treating type II diabetes.

Iozzo P.

Obesity is a phenotype resulting from a series of causative factors with a variable risk of complications. Etiologic diversity requires personalized prevention and treatment. Imaging procedures offer the potential to investigate the interplay between organs and pathways underlying energy intake and consumption in an integrated manner, and may open the perspective to classify and treat obesity according to causative mechanisms. This review illustrates the contribution provided by imaging studies to the understanding of human obesity, starting with the regulation of food intake and intestinal metabolism, followed by the role of adipose tissue in storing, releasing, and utilizing substrates, including the interconversion of white and brown fat, and concluding with the examination of imaging risk indicators related to complications, including type 2 diabetes, liver pathologies, cardiac and kidney diseases, and sleep disorders. The imaging modalities include (1) positron emission tomography to quantify organ-specific perfusion and substrate metabolism; (2) computed tomography to assess tissue density as an indicator of fat content and browning/ whitening; (3) ultrasounds to examine liver steatosis, stiffness, and inflammation; and (4) magnetic resonance techniques to assess blood oxygenation levels in the brain, liver stiffness, and metabolite contents (triglycerides, fatty acids, glucose, phosphocreatine, ATP, and acetylcarnitine) in a variety of organs.

Daniele G., Iozzo P., Molina-Carrion M., Lancaster J., Ciociaro D., Cersosimo E., Tripathy D., Triplitt C., Fox P., Musi N., DeFronzo R., Gastaldelli A.

Glucagon-like peptide 1 receptors (GLP-1Rs) have been found in the brain, but whether GLP-1R agonists (GLP-1RAs) influence brain glucose metabolism is currently unknown. The study aim was to evaluate the effects of a single injection of the GLP-1RA exenatide on cerebral and peripheral glucose metabolism in response to a glucose load. In 15 male subjects with HbA1c of 5.7 ± 0.1%, fasting glucose of 114 ± 3 mg/dL, and 2-h glucose of 177 ± 11 mg/dL, exenatide (5 μg) or placebo was injected in double-blind, randomized fashion subcutaneously 30 min before an oral glucose tolerance test (OGTT). The cerebral glucose metabolic rate (CMRglu) was measured by positron emission tomography after an injection of [18F]2-fluoro-2-deoxy-d-glucose before the OGTT, and the rate of glucose absorption (RaO) and disposal was assessed using stable isotope tracers. Exenatide reduced RaO0–60 min (4.6 ± 1.4 vs. 13.1 ± 1.7 μmol/min ⋅ kg) and decreased the rise in mean glucose0–60 min (107 ± 6 vs. 138 ± 8 mg/dL) and insulin0–60 min (17.3 ± 3.1 vs. 24.7 ± 3.8 mU/L). Exenatide increased CMRglu in areas of the brain related to glucose homeostasis, appetite, and food reward, despite lower plasma insulin concentrations, but reduced glucose uptake in the hypothalamus. Decreased RaO0–60 min after exenatide was inversely correlated to CMRglu. In conclusion, these results demonstrate, for the first time in man, a major effect of a GLP-1RA on regulation of brain glucose metabolism in the absorptive state.

Wang S., Zhai X., Li S., McCabe M.F., Wang X., Rong P.

Melatonin plays a protective role in type 2 diabetes (T2D) through regulation of glucose metabolism. Whether transcutaneous vagus nerve stimulation (taVNS) is antidiabetic and whether a modulated melatonin production is involved in the antidiabetic mechanism of taVNS is unknown. In this study, once daily 30min noninvasive taVNS was administered in Zucker diabetic fatty (ZDF, fa/fa) and Zucker lean (ZL, +/fa) littermates under anesthesia for 5 consecutive weeks. The acute and chronic influences of taVNS on the secretion of melatonin were studied as well as the effects of taVNS on blood glucose metabolism. We found that naïve ZDF rats develop hyperglycemia naturally with age. Each taVNS session would trigger a tidal secretion of melatonin both during and after the taVNS procedure and induce an acute two-phase glycemic change, a steep increase followed by a gradual decrease. Once daily taVNS sessions eventually reduced the glucose concentration to a normal level in seven days and effectively maintained the normal glycemic and plasma glycosylated hemoglobin (HbAlc) levels when applied for five consecutive weeks. These beneficial effects of taVNS also exist in pinealectomized rats, which otherwise would show overt and continuous hyperglycemia, hyperinsulinemia, and high HbAlc levels. We concluded that multiple taVNS sessions are antidiabetic in T2D through triggering of tidal secretion of melatonin. This finding may have potential importance in developing new approaches to the treatment of T2D, which is highly prevalent, incurable with any current approaches, and very costly to the world.

Areias M.F., Prada P.O.

Obesity is increasing worldwide and is triggered, at least in part, by enhanced caloric intake. Food intake is regulated by a complex mechanism involving the hypothalamus and hindbrain circuitries. However, evidences have showing that reward systems are also important in regulating feeding behavior. In this context, amygdala is considered a key extra-hypothalamic area regulating feeding behavior in human beings and rodents. This review focuses on the regulation of food intake by amygdala and the mechanisms of insulin resistance in this brain area. Similar to the hypothalamus the anorexigenic effect of insulin is mediated via PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B) pathway in the amygdala. Insulin decreases NPY (neuropeptide Y) and increases oxytocin mRNA levels in the amygdala. High fat diet and saturated fatty acids induce inflammation, ER (endoplasmic reticulum) stress and the activation of serine kinases such as PKCθ (protein kinase C theta), JNK (c-Jun N-terminal kinase) and IKKβ (inhibitor of nuclear factor kappa-B kinase beta) in the amygdala, which have an important role in insulin resistance in this brain region. Overexpressed PKCθ in the CeA (central nucleus of amygdala) of rats increases weight gain, food intake, insulin resistance and hepatic triglycerides content. The inhibition of ER stress ameliorates insulin action/signaling, increases oxytocin and decreases NPY gene expression in the amygdala of high fat feeding rodents. Those data suggest that PKCθ and ER stress are main mechanisms of insulin resistance in the amygdala of obese rats and play an important role regulating feeding behavior.

Caravaggio F., Borlido C., Hahn M., Feng Z., Fervaha G., Gerretsen P., Nakajima S., Plitman E., Chung J.K., Iwata Y., Wilson A., Remington G., Graff-Guerrero A.

Li S., Zhai X., Rong P., McCabe M.F., Wang X., Zhao J., Ben H., Wang S.

Depression and type 2 diabetes (T2D) are common comorbid diseases and highly prevalent in the clinical setting with an unclarified mechanism. Zucker diabetic fatty (ZDF, fa/fa) rats natively develop T2D with hyperglycemia and hyperinsulinemia. Here we studied whether ZDF rats also innately develop depression, what a correlation is between depression and T2D, whether insulin receptor (IR) expression is involved in, and whether transcutaneous auricular vagus nerve stimulation (taVNS) would be beneficial in amelioration of the comorbidity. Six week old male ZDF and Zucker lean (ZL, fa/+) littermates were randomly divided into naïve (ZDF, n = 6; ZL, n = 7) and taVNS (ZDF-taVNS, n = 8; ZL-taVNS, n = 6) groups. Once daily 30 min-taVNS sessions were administrated under anesthesia for 34 consecutive days in taVNS groups. Blood glucose levels were tested weekly, and plasma glycosylated hemoglobin (HbAlc) level and immobility time in forced swimming test were determined on day 35 in all groups. The expression of insulin receptor (IR) in various tissues was also detected by immunostaining and Western blot. We found that naïve ZDF rats developed hyperglycemia steadily. These ZDF rats showed a strong positive correlation between longer immobility time and higher plasma HbAlC level. Long term taVNS treatment simultaneously prevented the development of depression-like behavior and progression of hyperglycemia in ZDF rats. The expression of IR in various tissues of naïve ZDF rats is lower than in naïve ZL and long-term taVNS treated ZDF rats. Collectively, our results indicate that in ZDF rats, i) depression and T2D develop simultaneously, ii) immobility time and HbAlc concentrations are highly and positively correlated, iii) a low expression of IR may be involved in the comorbidity of depression and T2D, and iv) taVNS is antidiabetic and antidepressive possibly through IR expression upregulation.

Bodenlos J.S., Schneider K.L., Oleski J., Gordon K., Rothschild A.J., Pagoto S.L.

Background: Animal research suggests that vagus nerve stimulation (VNS) is associated with weight loss and decreased appetite. Results from human studies are mixed; some suggest that VNS affects weight whereas others do not, and it is unclear how VNS affects eating behaviors. Baseline body mass index (BMI) and VNS device settings may moderate the effects of VNS on caloric intake. This study investigates the association among BMI, VNS device settings, and caloric intake of highly palatable foods during VNS on versus VNS off sessions in 16 adult patients (62.5% female; BMI mean = 29.11 ± 6.65) using VNS therapy for either epilepsy or depression. Method: Participants attended 2 experimental sessions (VNS on versus off) where they were presented with 4 preferred snack foods totaling 1600 calories. At the start of the session, they either had their VNS devices turned off or left on. Caloric intake was calculated by weighing foods before and after each session. BMI category (overweight/obese and lean) was the between group factor in the analysis. Results: After controlling for covariates, an interaction of condition and BMI category ( P = .03) was found. There was an interaction of condition and device output current ( P = .05) and a trend toward an interaction of condition and device on time ( P = .07). Conclusions: Excess weight may impact how neurobiological signals from the vagus nerve affect appetite and eating. Future research is needed to further elucidate this relationship.

Goodpaster B.H., Bertoldo A., Ng J.M., Azuma K., Pencek R.R., Kelley C., Price J.C., Cobelli C., Kelley D.E.

Dynamic positron emission tomography (PET) imaging was performed using sequential tracer injections ([15O]H2O, [11C]3-O-methylglucose [3-OMG], and [18F]fluorodeoxyglucose [FDG]) to quantify, respectively, skeletal muscle tissue perfusion (glucose delivery), kinetics of bidirectional glucose transport, and glucose phosphorylation to interrogate the individual contribution and interaction among these steps in muscle insulin resistance (IR) in type 2 diabetes (T2D). PET imaging was performed in normal weight nondiabetic subjects (NW) (n = 5), obese nondiabetic subjects (OB) (n = 6), and obese subjects with T2D (n = 7) during fasting conditions and separately during a 6-h euglycemic insulin infusion at 40 mU·m−2·min−1. Tissue tracer activities were derived specifically within the soleus muscle with PET images and magnetic resonance imaging. During fasting, NW, OB, and T2D subjects had similar [11C]3-OMG and [18F]FDG uptake despite group differences for tissue perfusion. During insulin-stimulated conditions, IR was clearly evident in T2D (P < 0.01), and [18F]FDG uptake by muscle was inversely correlated with systemic IR (P < 0.001). The increase in insulin-stimulated glucose transport was less (P < 0.01) in T2D (twofold) than in NW (sevenfold) or OB (sixfold) subjects. The fractional phosphorylation of [18F]FDG during insulin infusion was also significantly lower in T2D (P < 0.01). Dynamic triple-tracer PET imaging indicates that skeletal muscle IR in T2D involves a severe impairment of glucose transport and additional impairment in the efficiency of glucose phosphorylation.

Immonen H., Hannukainen J.C., Iozzo P., Soinio M., Salminen P., Saunavaara V., Borra R., Parkkola R., Mari A., Lehtimäki T., Pham T., Laine J., Kärjä V., Pihlajamäki J., Nelimarkka L., et. al.

Bariatric surgery reduces weight and improves glucose metabolism in obese patients. We investigated the effects of bariatric surgery on hepatic insulin sensitivity.Twenty-three morbidly obese (nine diabetic and fourteen non-diabetic) patients and ten healthy, lean control subjects were studied using positron emission tomography to assess hepatic glucose uptake in the fasting state and during euglycemic hyperinsulinemia. Magnetic resonance spectroscopy was performed to measure liver fat content and magnetic resonance imaging to obtain liver volume. Obese patients were studied before bariatric surgery (either sleeve gastrectomy or Roux-en-Y gastric bypass) and six months after surgery.Insulin-induced hepatic glucose uptake was increased by 33% in non-diabetic and by 36% in diabetic patients at follow-up compared with baseline, but not totally normalized. The liver fat content was reduced by 76%, liver volume by 26% and endogenous glucose production by 19% in non-diabetic patients. The respective changes in diabetic patients were 73%, 24%, and 25%. Postoperatively, liver fat content and endogenous glucose production were almost normalized to lean controls, but liver volume remained greater than in control subjects.This study shows that bariatric surgery leads to a significant improvement in hepatic insulin sensitivity: insulin-stimulated hepatic glucose uptake was improved and endogenous glucose production reduced when measured, six-months, after surgery. These metabolic effects were accompanied by a marked reduction in hepatic volume and fat content. Overall, the gain in hepatic insulin sensitivity in diabetic patients was quite similar to non-diabetic patients for the same weight reduction.

Acosta A., Abu Dayyeh B.K., Port J.D., Camilleri M.

Despite advances in understanding the roles of adiposity, food intake, GI and adipocyte-related hormones, inflammatory mediators, the gut–brain axis and the hypothalamic nervous system in the pathophysiology of obesity, the effects of different therapeutic interventions on those pathophysiological mechanisms are controversial. There are still no low-cost, safe, effective treatments for obesity and its complications. Currently, bariatric surgical approaches targeting the GI tract are more effective than non-surgical approaches in inducing weight reduction and resolving obesity-related comorbidities. However, current guidelines emphasise non-surgical approaches through lifestyle modification and medications to achieve slow weight loss, which is not usually sustained and may be associated with medication-related side effects. This review analyses current central, peripheral or hormonal targets to treat obesity and addresses challenges and opportunities to develop novel approaches for obesity.

Hays S.A., Rennaker R.L., Kilgard M.P.

Pathological neural activity in a variety of neurological disorders could be treated by directing plasticity to specifically renormalize aberrant neural circuits, thereby restoring normal function. Brief bursts of acetylcholine and norepinephrine can enhance the neural plasticity associated with coincident events. Vagus nerve stimulation (VNS) represents a safe and effective means to trigger the release of these neuromodulators with a high degree of temporal control. VNS-event pairing can generate highly specific and long-lasting plasticity in sensory and motor cortex. Based on the capacity to drive specific changes in neural circuitry, VNS paired with experience has been successful in effectively ameliorating animal models of chronic tinnitus, stroke, and posttraumatic stress disorder. Targeted plasticity therapy utilizing VNS is currently being translated to humans to treat chronic tinnitus and improve motor recovery after stroke. This chapter will discuss the current progress of VNS paired with experience to drive specific plasticity to treat these neurological disorders and will evaluate additional future applications of targeted plasticity therapy.

Vijgen G.H., Bouvy N.D., Leenen L., Rijkers K., Cornips E., Majoie M., Brans B., van Marken Lichtenbelt W.D.

Background Human brown adipose tissue (BAT) activity is inversely related to obesity and positively related to energy expenditure. BAT is highly innervated and it is suggested the vagus nerve mediates peripheral signals to the central nervous system, there connecting to sympathetic nerves that innervate BAT. Vagus nerve stimulation (VNS) is used for refractory epilepsy, but is also reported to generate weight loss. We hypothesize VNS increases energy expenditure by activating BAT. Methods and Findings Fifteen patients with stable VNS therapy (age: 45±10yrs; body mass index; 25.2±3.5 kg/m2) were included between January 2011 and June 2012. Ten subjects were measured twice, once with active and once with inactivated VNS. Five other subjects were measured twice, once with active VNS at room temperature and once with active VNS under cold exposure in order to determine maximal cold-induced BAT activity. BAT activity was assessed by 18-Fluoro-Deoxy-Glucose-Positron-Emission-Tomography-and-Computed-Tomography. Basal metabolic rate (BMR) was significantly higher when VNS was turned on (mean change; +2.2%). Mean BAT activity was not significantly different between active VNS and inactive VNS (BAT SUVMean; 0.55±0.25 versus 0.67±0.46, P = 0.619). However, the change in energy expenditure upon VNS intervention (On-Off) was significantly correlated to the change in BAT activity (r = 0.935, P

Nagai M., Rommel K., Po S.S., Dasari T.W.

Metabolic syndrome (MetS) induces a systemic inflammatory state which can lead to cardiomyopathy, manifesting clinically as heart failure (HF) with preserved ejection fraction (HFpEF). MetS components are intricately linked to the pathophysiologic processes of myocardial remodeling. Increased sympathetic nervous system activity, which is noted as an upstream factor of MetS, has been linked to adverse myocardial structural changes. Since renal denervation and vagus nerve stimulation have a sympathoinhibitory effect, attention has been paid to the cardioprotective effects of autonomic neuromodulation. In this review, the pathophysiology underlying the relationship between MetS and HF is elucidated, and the evidence regarding autonomic neuromodulation in HFpEF is summarized.

Yang S., Chen L., Luo D., Wang Y., Liang F.

Obesity, a widespread global health issue, is frequently linked to disrupted lipid metabolism, resulting in excessive accumulation of adipose tissue and associated health complications. Acupuncture, a traditional Chinese medical modality, has exhibited potential as a viable intervention for addressing obesity. The underlying mechanism proposed involves the stimulation of specific acupoints to exert a regulatory influence on hepatic function. The liver has a central role in lipid metabolism, including processes such as lipid synthesis, storage and distribution. Acupuncture is believed to enhance the liver's efficiency in processing lipids, thereby reducing lipid accumulation and improving metabolic functions. Research indicates that acupuncture can influence the expression of certain genes and proteins involved in lipid metabolism in the liver. This includes upregulating genes that promote lipid breakdown and oxidation, and downregulating those involved in lipid synthesis. Additionally, acupuncture has been shown to improve insulin sensitivity, which is crucial for the regulation of lipid metabolism. Furthermore, the potential anti-inflammatory effects of acupuncture may play a significant role in its efficacy for the treatment of obesity. The presence of chronic inflammation has been strongly associated with metabolic disorders such as obesity. Through its ability to mitigate inflammation, acupuncture can potentially aid in the restoration of lipid metabolism and the reduction of body weight. Moreover, the amelioration of hepatic oxidative stress represents another mechanism by which acupuncture may contribute to the reduction of lipid deposition. Notably, the liver, being the primary site of lipid metabolism, maintains communication with various organs including the brain, adipose tissue, skeletal muscle and intestines. This perspective opens new avenues for the treatment of obesity, emphasizing the importance of holistic approaches in managing complex metabolic disorders. Please cite this article as: Yang SR, Chen L, Luo D, Wang YY, Liang FX. Unlocking the potential: How acupuncture reshapes the liver-centered lipid metabolism pattern to fight obesity. J Integr Med. 2024; Epub ahead of print.

Xue R., Wu Q., Guo L., Ye D., Cao Q., Zhang M., Xian Y., Chen M., Yan K., Zheng J.

AbstractObesity is a major cause of nonalcohol fatty liver disease (NAFLD), which is characterized by hepatic fibrosis, lipotoxicity, inflammation, and apoptosis. Previous studies have shown that an imbalance in the autonomic nervous system is closely related to the pathogenesis of NAFLD. In this study, we investigated the effects of pyridostigmine (PYR), a cholinesterase (AChE) inhibitor, on HFD‐induced liver injury and explored the potential mechanisms involving mitochondrial damage and oxidative stress. A murine model of HFD‐induced obesity was established using the C57BL/6 mice, and PYR (3 mg/kg/d) or placebo was administered for 20 weeks. PYR reduced the body weight and liver weight of the HFD‐fed mice. Additionally, the serum levels of IL‐6, TNF‐α, cholesterol, and triglyceride were significantly lower in the PYR‐treated versus the untreated mice, corresponding to a decrease in hepatic fibrosis, lipid accumulation, and apoptosis in the former. Furthermore, the mitochondrial morphology improved significantly in the PYR‐treated group. Consistently, PYR upregulated ATP production and the mRNA level of the mitochondrial dynamic factors OPA1, Drp1 and Fis1, and the mitochondrial unfolded protein response (UPRmt) factors LONP1 and HSP60. Moreover, PYR treatment activated the Keap1/Nrf2 pathway and upregulated HO‐1 and NQO‐1, which mitigated oxidative injury as indicated by decreased 8‐OHDG, MDA and H2O2 levels, and increased SOD activity. Finally, PYR elevated acetylcholine (ACh) levels by inhibiting AChE, and upregulated the α7nAChR and M3AChR proteins in the HFD‐fed mice. PYR alleviated obesity‐induced hepatic injury in mice by mitigating mitochondrial damage and oxidative stress via α7nAChR and M3AChR.

Elkattawy H.A., Mahmoud S.M., Hassan A.E., Behiry A., Ebrahim H.A., Ibrahim A.M., Zaghamir D.E., El-Sherbiny M., El-Sayed S.F.

Background: The harmful consequences of non-alcoholic fatty liver disease (NAFLD) are posing an increasing threat to public health as the incidence of diabetes and obesity increases globally. A non-invasive treatment with a range of autonomic and metabolic benefits is transcutaneous vagus nerve stimulation (tVNS). Aim of the study: To investigate the possible preventive impacts of VNS against adult rats’ NAFLD caused by a high-fat diet (HFD) and to clarify the underlying mechanisms. Methods: A total of thirty-two adult male rats were split into two groups: the HFD-induced NAFLD group (n = 24) and the control normal group (n = 8). The obesogenic diet was maintained for 12 weeks to induce hepatic steatosis. The HFD-induced NAFLD group (n = 24) was separated into three groups: the group without treatment (n = 8), the group with sham stimulation (n = 8), and the group with VNS treatment (n = 8). VNS was delivered for 30 min per day for 6 weeks after the establishment of NAFLD using a digital TENS device. The subsequent assessments included hepatic triglyceride, cholesterol content, serum lipid profile, and liver function testing. In this context, inflammatory biomarkers (TNF-α, IL-6) and hepatic oxidative stress (MDA, SOD, and GPx) were also assessed. To clarify the possible mechanisms behind the protective benefits of VNS, additional histological inspection and immunohistochemistry analysis of TNF-α and Caspase-3 were performed. Results: In the NAFLD-affected obese rats, VNS markedly decreased the rats’ body mass index (BMI) and abdominal circumference (AC). Liver function markers (albumin, ALT, and AST) and the serum lipid profile—which included a notable decrease in the amounts of hepatic triglycerides and cholesterol—were both markedly improved. Additionally, oxidative stress and inflammatory indicators showed a considerable decline with VNS. Notably, the liver tissues examined by histopathologists revealed that there is evidence of the protective impact of VNS on the oxidative and inflammatory states linked to HFD-induced NAFLD while maintaining the architectural and functional condition of the liver. Conclusions: Our findings suggest that VNS may represent a promising therapeutic candidate for managing NAFLD induced by obesity. It can be considered to be an effective adjuvant physiological intervention for the obese population with NAFLD to spare the liver against obesity-induced deleterious injury.

Leinen M., Grandy E.F., Gebel L.M., Santana T.M., Rodriguez A.L., Singh S.K., Fernandez M.I., Dalugdug J.C., Garcia-Colon E.M., Lybeshari K., Alexander D.R., Maura M.I., Gonzalez M.D., De Paula Cunha Almeida C., Anyaso-Samuel S., et. al.

Abstract Introduction Obesity affects millions of Americans. The vagal nerves convey the degree of stomach fullness to the brain via afferent visceral fibers. Studies have found that vagal nerve stimulation (VNS) promotes reduced food intake, causes weight loss, and reduces cravings and appetite. Methods Here, we evaluate the efficacy of a novel stimulus waveform applied bilaterally to the subdiaphragmatic vagal nerve stimulation (sVNS) for almost 13 weeks. A stimulating cuff electrode was implanted in obesity-prone Sprague Dawley rats maintained on a high-fat diet. Body weight, food consumption, and daily movement were tracked over time and compared against three control groups: sham rats on a high-fat diet that were implanted with non-operational cuffs, rats on a high-fat diet that were not implanted, and rats on a standard diet that were not implanted. Results Results showed that rats on a high-fat diet that received sVNS attained a similar weight to rats on a standard diet due primarily to a reduction in daily caloric intake. Rats on a high-fat diet that received sVNS had significantly less body fat than other high-fat controls. Rats receiving sVNS also began moving a similar amount to rats on the standard diet. Conclusion Results from this study suggest that bilateral subdiaphragmatic vagal nerve stimulation can alter the rate of growth of rats maintained on a high-fat diet through a reduction in daily caloric intake, returning their body weight to that which is similar to rats on a standard diet over approximately 13 weeks. Graphical Abstract

Hoornenborg C.W., van Dijk T.H., Bruggink J.E., Beek van A.P., Dijk van G.

The sub-diaphragmatic vagus innervates various organs involved in the control of glucose homeostasis including the liver, pancreas and the intestines. In the current study, we investigated the effect of acute electrical stimulation of the anterior trunk of the sub-diaphragmatic vagus on glucose fluxes in anaesthetized adult male rats. After overnight fast, rats underwent either vagus nerve stimulation (VNS+, n=11; rectangular pulses at 5 Hz, 1.5 mA, 1 msec pulse width) or sham stimulation (VNS-; n=11) for 120 minutes under isoflurane anesthesia. Before stimulation, the rats received an i.v. bolus of stable isotope labelled glucose [6,6-2H2]glucose. Endogenous glucose production (EGP) and glucose clearance rate (GCR) were calculated by kinetic analysis from the wash-out of injected D-[6,6-2H2]glucose from the circulation. VNS+ resulted in lower glucose levels compared to the VNS- group (p

Özden A.V.

Although vagus nerve stimulation (VNS) is nowadays frequently used in the treatment of neuropsychiatric disorders including epilepsy, depression, and chronic pain such as migraine, an increasing number of studies mention its peripheral effects. Central effects of VNS as a cranial neuromodulation method can be prioritized, but it can cause physiological changes in many peripheral organs as well by the autonomic nervous system (ANS) activity modification. It can be argued that the peripheral effects of VNS can occur through many mechanisms such as reducing hyperinflammation, regulating circulation, determining the level of muscle tone, and controlling endocrine and exocrine secretions. In addition, the role of the vagus nerve on the gut-brain axis should always be kept in mind. However, the wide distribution of the vagus nerve and its extensive connections including those in the central nervous system complicate our understanding of its peripheral effects. VNS appears to have effects on the body (metabolism, neuronal activity, immune status, etc.) but we need more randomized placebo-controlled studies to fully understand and demonstrate the effects of VNS on peripheral targets. Biofeedback systems can be useful both for testing different stimulation parameters and for better understanding of peripheral effects.

Mogi M., Tanaka A., Node K., Tomitani N., Hoshide S., Narita K., Nozato Y., Katsurada K., Maruhashi T., Higashi Y., Matsumoto C., Bokuda K., Yoshida Y., Shibata H., Toba A., et. al.

Total 276 manuscripts were published in Hypertension Research in 2022. Here our editorial members picked up the excellent papers, summarized the current topics from the published papers and discussed future perspectives in the sixteen fields. We hope you enjoy our special feature, 2023 update and perspectives in Hypertension Research.

Zhang S., He H., Wang Y., Wang X., Liu X.

AbstractPolycystic ovary syndrome (PCOS) is a common endocrine disorder in women of childbearing age. The etiology of PCOS is multifactorial, and current treatments for PCOS are far from satisfactory. Recently, an imbalanced autonomic nervous system (ANS) with sympathetic hyperactivity and reduced parasympathetic nerve activity (vagal tone) has aroused increasing attention in the pathogenesis of PCOS. In this paper, we review an innovative therapy for the treatment of PCOS and related co-morbidities by targeting parasympathetic modulation based on non-invasive transcutaneous auricular vagal nerve stimulation (ta-VNS). In this work, we present the role of the ANS in the development of PCOS and describe a large number of experimental and clinical reports that support the favorable effects of VNS/ta-VNS in treating a variety of symptoms, including obesity, insulin resistance, type 2 diabetes mellitus, inflammation, microbiome dysregulation, cardiovascular disease, and depression, all of which are also commonly present in PCOS patients. We propose a model focusing on ta-VNS that may treat PCOS by (1) regulating energy metabolism via bidirectional vagal signaling; (2) reversing insulin resistance via its antidiabetic effect; (3) activating anti-inflammatory pathways; (4) restoring homeostasis of the microbiota-gut-brain axis; (5) restoring the sympatho-vagal balance to improve CVD outcomes; (6) and modulating mental disorders. ta-VNS is a safe clinical procedure and it might be a promising new treatment approach for PCOS, or at least a supplementary treatment for current therapeutics.

Mylavarapu R.V., Kanumuri V.V., de Rivero Vaccari J.P., Misra A., McMillan D.W., Ganzer P.D.

AbstractIn recent decades, vagus nerve stimulation (VNS) therapy has become widely used for clinical applications including epilepsy, depression, and enhancing the effects of rehabilitation. However, several questions remain regarding optimization of this therapy to maximize clinical outcomes. Although stimulation parameters such as pulse width, amplitude, and frequency are well studied, the timing of stimulation delivery both acutely (with respect to disease events) and chronically (over the timeline of a disease’s progression) has generally received less attention. Leveraging such information would provide a framework for the implementation of next generation closed-loop VNS therapies. In this mini-review, we summarize a number of VNS therapies and discuss (1) general timing considerations for these applications and (2) open questions that could lead to further therapy optimization.

Sudhakaran G., Rajesh R., Guru A., Arasu M.V., Gopinath P., Arockiaraj J.

Excess accumulation of lipids leads to obesity. Triterpenoids are a group of plant compounds which poses various biological activities. The biological activities of Nimbin analogs N5 and N7 were addressed in this study on inhibiting lipid aggregation and underlying the derivatives molecular mechanisms for a therapeutical approach.This study aims to evaluate the anti-adipogenic activity of semi-natural Nimbin analogs, N5 and N7, on zebrafish larvae induced with oxidative stress due to a high-fat diet (HFD) and adipogenesis using specific fluorescent stains.Zebrafish at 4 days post fertilized (dpf) larvae were divided into groups for the HFD diet along with exposure to various concentrations of N5 and N7. HFD induced accumulation of neutral lipids and triglycerides (Oil Red O and Nile red staining, respectively) with weight gain, which generated intracellular ROS (DCFH-DA staining) and superoxide anion production (DHE staining) with depleted glutathione levels (NDA staining) were assayed. HFD exposure promoted the accumulation of inflammatory macrophages (Neutral red staining) and impaired glucose metabolism (2NBDG staining). The ability of N5 and N7 to reduce total regulating lipogenic specific genes C/EBP-α, SREBP-1 and FAS were evaluated using relative gene expression.The Nimbin analogues N5 and N7 suppressed adipogenesis, forming intracellular ROS and superoxide anion while simultaneously restoring glutathione levels. The analogues significantly lowered total TC and TG levels, prevented inflammatory macrophage build-up and boosted glucose absorption. Also, N5 and N7 down-regulate the lipogenic-specific genes.Nimbin analogs N5 and N7 enhance lipolysis and inhibit adipogenesis in in-vivo zebrafish larvae model.

Waataja J.J., Nihalani R.K., Honda C.N., Billington C.J.

BackgroundThere is an unmet need for new type 2 diabetes treatments providing improved efficacy, durability and customized to improve patient’s compliance. Bio-electronic neuromodulation of Vagus nerve branches innervating organs that regulate plasma glucose, may be a method for treating type 2 diabetes. The pancreas has been shown to release insulin during Vagus stimulation. The hepatic vagal branch, innervating the liver, has been shown to decrease glucose release and decrease insulin resistance following ligation. However, standalone stimulation of the Vagus nerve has shown mixed results and Vagus nerve ligation has undesirable effects. Little is known; however, of the effect on plasma glucose with combined neuromodulation consisting of stimulation of the celiac branch innervating the pancreas with simultaneous high frequency alternating current (HFAC) blockade of the hepatic branch. This study tested the effects of this approach on increasing glycemic control in rat a model of type 2 diabetes and Alloxan treated swine.Materials and methodsZucker obese (fatty) male rats (ZDF fa/fa) were used as a model of type 2 diabetes as well as glucose intolerant Alloxan treated swine. In ZDF rat experiments glycemic control was accessed with an intravenous glucose tolerance test during HFAC-induced hepatic branch block with concurrent celiac stimulation (HFAC + stimulation). In swine experiments glycemic control was accessed by an oral glucose tolerance test during HFAC + stimulation. Insulin measurements were taken prior to and following swine experiments giving insight into beta cell exhaustion. Histopathology was conducted to determine safety of HFAC + stimulation on Vagal branches.ResultsZucker rats demonstrated a significant improvement to an intravenous glucose tolerance test during HFAC + stimulation compared to sham. There was no significant difference from sham compared to hepatic vagotomy or celiac stimulation. In Alloxan treated swine, when subjected to HFAC + stimulation, there was a significant improvement in glycemic control as measured by an improvement on oral glucose tolerance tests and a decrease in fasting plasma glucose. Insulin responses were similar prior to and following HFAC + stimulation experiments. Histopathology demonstrated healthy swine Vagus nerves.ConclusionElectrical blockade of the hepatic Vagus branch with simultaneous stimulation of the celiac Vagus branch may be a novel, adjustable and localized approach for a treatment of type 2 diabetes.

Kiselev A.R., Schwartz E.N., Dzhioeva O.N., Drapkina O.M.

Пандемия ожирения становится все более актуальной проблемой современной медицины, обусловливая необходимость развития новых подходов к коррекции избыточной массы тела. К таковым относится электрическая стимуляция блуждающего нерва, возможности клинического применения которой активно изучают во всем мире. В обзоре обсуждаются современные представления о физиологических основах коррекции избыточной массы тела с использованием чрескожной стимуляции блуждающего нерва.

Zhang X., Guérin S., Launay Y., Serrand Y., Coquery N., Val-Laillet D.

This study aimed to compare the gut-brain axis responses to acute electroacupuncture (EA) at different acupoint combinations in the minipig model. Four adult Yucatan minipigs were subjected twice to four acute EA treatments (25-minute acute sessions) including sham (false acupoints) and control (no EA), during anesthesia and according to a Latin-square design paradigm. Acupoint combinations (4 loci each) are head-abdomen (#70 Dafengmen, #35 Sanwan), back (bilateral #27 Pishu, #28 Weishu), leg (bilateral #79 Hangou, #63 Housanli), and sham (2 bilateral points that are not acupoints). Electrocardiograms were performed to explore heart rate variability (HRV). Infrared thermography was used to measure skin temperature at the stimulation points. Saliva (cortisol) and blood samples (leptin, total/active ghrelin, insulin, and glucose) were collected for further analyses before and after acute EA. All animals were also subjected to BOLD fMRI to investigate the brain responses to EA. Acute EA significantly modulated several physiological and metabolic parameters compared to basal, sham, and/or control conditions, with contrasting effects in terms of BOLD responses in brain regions involved in the hedonic and cognitive control of food intake. The head-abdomen combination appeared to be the most promising combination in terms of brain modulation of the corticostriatal circuit, with upregulation of the dorsolateral prefrontal cortex, dorsal striatum, and anterior cingulate cortex. It also induced significantly lower plasma ghrelin levels compared to sham, suggesting anorectic effects, as well as no temperature drop at the stimulation site. This study opens the way to a further preclinical trial aimed at investigating chronic EA in obese minipigs.

Cotero V., Graf J., Miwa H., Hirschstein Z., Qanud K., Huerta T.S., Tai N., Ding Y., Jimenez-Cowell K., Tomaio J.N., Song W., Devarajan A., Tsaava T., Madhavan R., Wallace K., et. al.

Peripheral neurons that sense glucose relay signals of glucose availability to integrative clusters of neurons in the brain. However, the roles of such signalling pathways in the maintenance of glucose homoeostasis and their contribution to disease are unknown. Here we show that the selective activation of the nerve plexus of the hepatic portal system via peripheral focused ultrasound stimulation (pFUS) improves glucose homoeostasis in mice and rats with insulin-resistant diabetes and in swine subject to hyperinsulinemic-euglycaemic clamps. pFUS modulated the activity of sensory projections to the hypothalamus, altered the concentrations of metabolism-regulating neurotransmitters, and enhanced glucose tolerance and utilization in the three species, whereas physical transection or chemical blocking of the liver–brain nerve pathway abolished the effect of pFUS on glucose tolerance. Longitudinal multi-omic profiling of metabolic tissues from the treated animals confirmed pFUS-induced modifications of key metabolic functions in liver, pancreas, muscle, adipose, kidney and intestinal tissues. Non-invasive ultrasound activation of afferent autonomic nerves may represent a non-pharmacologic therapy for the restoration of glucose homoeostasis in type-2 diabetes and other metabolic diseases. Selective activation of the hepatoportal nerve plexus via peripheral focused ultrasound stimulation improves glucose homoeostasis and enhances glucose tolerance and utilization in rodent models of diabetes and in swine.