Canagliflozin, a sodium glucose cotransporter 2 inhibitor, attenuates obesity-induced inflammation in the nodose ganglion, hypothalamus, and skeletal muscle of mice.

Chronic inflammation in systemic organs, such as adipose tissue, nodose ganglion, hypothalamus, and skeletal muscles, is closely associated with obesity and diabetes mellitus. Because sodium glucose cotransporter 2 (SGLT2) inhibitors exert both anti-diabetic and anti-obesity effects by promoting urinary excretion of glucose and subsequent caloric loss, we investigated the effect of canagliflozin, an SGLT2 inhibitor, on obesity-induced inflammation in neural tissues and skeletal muscles of mice. High-fat diet (HFD)-fed male C57BL/6J mice were treated with canagliflozin for 8 weeks. Canagliflozin attenuated the HFD-mediated increases in body weight, liver weight, and visceral and subcutaneous fat weight. Additionally, canagliflozin decreased blood glucose as well as the fat, triglyceride, and glycogen contents of the liver. Along with these metabolic corrections, canagliflozin attenuated the increases in the mRNA levels of the proinflammatory biomarkers Iba1 and Il6 and the number of macrophages/microglia in the nodose ganglion and hypothalamus. In the skeletal muscle of HFD-fed obese mice, canagliflozin decreased inflammatory cytokine levels, macrophage accumulation, and the mRNA level of the specific atrophic factor atrogin-1. Canagliflozin also increased the mRNA level of insulin-like growth factor 1, protected against muscle mass loss, and restored the contractile force of muscle. These findings suggested that SGLT2 inhibition disrupts the vicious cycle of obesity and inflammation, not only by promoting caloric loss, but also by suppression of obesity-related inflammation in both the nervous system and skeletal muscle.

Naznin F ，Sakoda H ，Okada T ，Tsubouchi H ，Waise TM ，Arakawa K ，Nakazato M ... -  《-》

SGLT2 Inhibition by Empagliflozin Promotes Fat Utilization and Browning and Attenuates Inflammation and Insulin Resistance by Polarizing M2 Macrophages in Diet-induced Obese Mice.

Sodium-glucose cotransporter (SGLT) 2 inhibitors increase urinary glucose excretion (UGE), leading to blood glucose reductions and weight loss. However, the impacts of SGLT2 inhibition on energy homeostasis and obesity-induced insulin resistance are less well known. Here, we show that empagliflozin, a SGLT2 inhibitor, enhanced energy expenditure and attenuated inflammation and insulin resistance in high-fat-diet-induced obese (DIO) mice. C57BL/6J mice were pair-fed a high-fat diet (HFD) or a HFD with empagliflozin for 16weeks. Empagliflozin administration increased UGE in the DIO mice, whereas it suppressed HFD-induced weight gain, insulin resistance, and hepatic steatosis. Moreover, empagliflozin shifted energy metabolism towards fat utilization, elevated AMP-activated protein kinase and acetyl-CoA carbolxylase phosphorylation in skeletal muscle, and increased hepatic and plasma fibroblast growth factor 21 levels. Importantly, empagliflozin increased energy expenditure, heat production, and the expression of uncoupling protein 1 in brown fat and in inguinal and epididymal white adipose tissue (WAT). Furthermore, empagliflozin reduced M1-polarized macrophage accumulation while inducing the anti-inflammatory M2 phenotype of macrophages within WAT and liver, lowering plasma TNFα levels and attenuating obesity-related chronic inflammation. Thus, empagliflozin suppressed weight gain by enhancing fat utilization and browning and attenuated obesity-induced inflammation and insulin resistance by polarizing M2 macrophages in WAT and liver.

Xu L ，Nagata N ，Nagashimada M ，Zhuge F ，Ni Y ，Chen G ，Mayoux E ，Kaneko S ，Ota T ... -  《EBioMedicine》

One-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice.

A high-fat diet (HFD) induces inflammation in systemic organs including the hypothalamus, resulting in obesity and diabetes. The vagus nerve connects the visceral organs and central nervous system, and the gastric-derived orexigenic peptide ghrelin transmits its starvation signals to the hypothalamus via the vagal afferent nerve. Here we investigated the inflammatory response in vagal afferent neurons and the hypothalamus in mice following one day of HFD feeding. This treatment increased the number of macrophages/microglia in the nodose ganglion and hypothalamus. Furthermore, one-day HFD induced expression of Toll-like receptor 4 in the goblet cells of the colon and upregulated mRNA expressions of the proinflammatory biomarkers Emr1, Iba1, Il6, and Tnfα in the nodose ganglion and hypothalamus. Both subcutaneous administration of ghrelin and celiac vagotomy reduced HFD-induced inflammation in these tissues. HFD intake triggered inflammatory responses in the gut, nodose ganglion, and subsequently in the hypothalamus within 24 h. These findings suggest that the vagal afferent nerve may transfer gut-derived inflammatory signals to the hypothalamus via the nodose ganglion, and that ghrelin may protect against HFD-induced inflammation.

Waise TMZ ，Toshinai K ，Naznin F ，NamKoong C ，Md Moin AS ，Sakoda H ，Nakazato M ... -  《-》

Inhibition of the sodium-glucose co-transporter SGLT2 by canagliflozin ameliorates diet-induced obesity by increasing intra-adipose sympathetic innervation.

Inhibition of the sodium-glucose cotransporter 2 (SGLT2) induces hypoglycaemia by increasing urinary glucose excretion and increasing the use of fat. However, the underlying mechanism is poorly understood. This study was aimed to determine the effects of canagliflozin, a selective SGLT2 inhibitor, on diet-induced obesity and the underlying mechanism(s). Adult C57BL/6J male mice were fed with a standard chow diet or high-fat diet supplemented with vehicle or canagliflozin. Whole body energy expenditure was monitored by metabolic cages, noradrenaline levels were measured by HPLC, glucose uptake was measured by PET/CT, and mRNA and protein expression were measured by RT-PCR and western blotting analysis. Mice treated with canagliflozin were resistant to high-fat diet-induced obesity and its metabolic consequences. Canagliflozin treatment decreased fat mass and increased energy expenditure via increasing thermogenesis and lipolysis in adipose tissue. Mechanistically, SGLT2 inhibition by canagliflozin elevated adipose sympathetic innervation and fat mobilization via a β3 -adrenoceptor-cAMP-PKA signalling pathway. Finally, we showed that canagliflozin improved insulin resistance and hepatic steatosis in mice fed with a high-fat diet. Chronic inhibition of SGLT2 increased energy consumption by increasing intra-adipose sympathetic innervation to counteract diet-induced obesity. The present study reveals a new therapeutic function for SGLT2 inhibitors in regulating energy homeostasis.

Yang X ，Liu Q ，Li Y ，Ding Y ，Zhao Y ，Tang Q ，Wu T ，Chen L ，Pu S ，Cheng S ，Zhang J ，Zhang Z ，Huang Y ，Li R ，Zhao Y ，Zou M ，Shi X ，Jiang W ，Wang R ，He J ... -  《-》

Canagliflozin ameliorates obesity by improving mitochondrial function and fatty acid oxidation via PPARα in vivo and in vitro.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reported to significantly reduce body weight. This study investigated whether SGLT2 inhibitors directly affect adipose tissues and the underlying mechanisms in vivo and in vitro. Male C57BL/6 mice were fed a normal diet, high-fat diet (HFD), or HFD with canagliflozin for 14 weeks. 3T3-L1 adipocytes were treated with canagliflozin. Metabolic parameters were measured. Canagliflozin reduced body weight, fat mass, and white adipose tissue (WAT) weight and inhibited adipocyte hypertrophy. Canagliflozin improved glucose and lipid metabolic disorders induced by HFD. Furthermore, canagliflozin treatment reversed the suppressed mRNA and protein expression of PGC-1α, NRF1, tfam and CPT1b, which are markers of mitochondrial biogenesis, function and fatty acid oxidation in mice with obesity. In vitro, canagliflozin increased mitochondrial DNA to nuclear DNA and upregulated the expression of PGC-1α, NRF1, tfam, COX5b, COX8b, Atp5o, and CPT1b mRNA and PGC-1α, NRF1, tfam, COX5b, CPT1b protein in 3T3-L1 adipocytes in a dose-dependent manner, while these increases were inhibited by GW6471, a PPARα antagonist. Our study showed that canagliflozin protected against HFD-induced obesity and obesity-related metabolic disorders by improving mitochondrial function and fatty acid oxidation in adipose tissue and adipocytes. Such energy-dissipating effects of canagliflozin may be mediated by PPARα.

Wei D ，Liao L ，Wang H ，Zhang W ，Wang T ，Xu Z ... -  《-》