Semaglutide, a glucagon-like peptide 1 (GLP-1) analog, induces weight loss, lowers glucose levels, and reduces cardiovascular risk in patients with diabetes. Mechanistic preclinical studies suggest weight loss is mediated through GLP-1 receptors (GLP-1Rs) in the brain. The findings presented here show that semaglutide modulated food preference, reduced food intake, and caused weight loss without decreasing energy expenditure. Semaglutide directly accessed the brainstem, septal nucleus, and hypothalamus but did not cross the blood-brain barrier; it interacted with the brain through the circumventricular organs and several select sites adjacent to the ventricles. Semaglutide induced central c-Fos activation in 10 brain areas, including hindbrain areas directly targeted by semaglutide, and secondary areas without direct GLP-1R interaction, such as the lateral parabrachial nucleus. Automated analysis of semaglutide access, c-Fos activity, GLP-1R distribution, and brain connectivity revealed that activation may involve meal termination controlled by neurons in the lateral parabrachial nucleus. Transcriptomic analysis of microdissected brain areas from semaglutide-treated rats showed upregulation of prolactin-releasing hormone and tyrosine hydroxylase in the area postrema. We suggest semaglutide lowers body weight by direct interaction with diverse GLP-1R populations and by directly and indirectly affecting the activity of neural pathways involved in food intake, reward, and energy expenditure.
Sanaz Gabery, Casper G. Salinas, Sarah J. Paulsen, Jonas Ahnfelt-Rønne, Tomas Alanentalo, Arian F. Baquero, Stephen T. Buckley, Erzsébet Farkas, Csaba Fekete, Klaus S. Frederiksen, Hans Christian C. Helms, Jacob F. Jeppesen, Linu M. John, Charles Pyke, Jane Nøhr, Tess T. Lu, Joseph Polex-Wolf, Vincent Prevot, Kirsten Raun, Lotte Simonsen, Gao Sun, Anett Szilvásy-Szabó, Hanni Willenbrock, Anna Secher, Lotte Bjerre Knudsen
A GLP-2 analogue is used in individuals with intestinal failure at risk for liver disease, yet the hepatic actions of GLP-2 are not understood. Treatment of high fat diet (HFD)-fed mice with GLP-2 did not modify development of hepatosteatosis or hepatic inflammation. In contrast, Glp2r-/- mice exhibited increased hepatic lipid accumulation, deterioration in glucose tolerance, and upregulation of biomarkers of hepatic inflammation. Both mouse and human liver expressed the canonical GLP-2R, and hepatic Glp2r expression was upregulated in mice with hepatosteatosis. Cell fractionation localized the Glp2r to hepatic stellate cells (HSC), and markers of HSC activation and fibrosis were increased in livers from Glp2r-/- mice. Moreover, GLP-2 directly modulated gene expression in isolated HSCs ex vivo. Taken together, these findings define an essential role for the GLP-2R in hepatic adaptation to nutrient excess and unveil a gut hormone-HSC axis, linking GLP-2R signaling to control of hepatic stellate cell activation.
Shai Fuchs, Bernardo Yusta, Laurie L. Baggio, Elodie M. Varin, Dianne Matthews, Daniel J. Drucker
Background: Metabolic disorders such as type 2 diabetes have been associated with a decrease in insulin pulse frequency and amplitude. We hypothesized that the T-allele at rs7903146 in TCF7L2, previously associated with β–cell dysfunction, would be associated with changes in these insulin pulse characteristics. Methods: 29 nondiabetic subjects (age = 46 ± 2, BMI = 28 ± 1 Kg/M2) participated in this study. Of these, 16 were homozygous for the C allele at rs7903146 and 13 were homozygous for the T allele. Deconvolution of peripheral C-peptide concentrations allowed the reconstruction of portal insulin secretion over time. This data was used for subsequent analyses. Pulse orderliness was assessed by Approximate Entropy (ApEn) and the dispersion of insulin pulses was measured by a Frequency Dispersion Index (FDI) applied to a Fourier Transform of individual insulin secretion rates. Results: During fasting conditions, the CC genotype group exhibited decreased pulse disorderliness compared to the TT genotype group (1.10 ± 0.03 vs. 1.19 ± 0.04, p = 0.03). FDI decreased in response to hyperglycemia in the CC genotype group, perhaps reflecting less entrainment of insulin secretion during fasting.Conclusion: Diabetes-associated variation in TCF7L2 is associated with decreased orderliness and pulse dispersion unchanged by hyperglycemia. Quantification of ApEn and FDI could represent novel markers of β-cell health.
Marcello C. Laurenti, Chiara Dalla Man, Ron T. Varghese, James C. Andrews, Robert A. Rizza, Aleksey Matveyenko, Giuseppe De Nicolao, Claudio Cobelli, Adrian Vella
Leptin receptor (LepRb)-expressing neurons of the nucleus tractus solitarius (NTS; LepRbNTS neurons) receive gut signals that synergize with leptin action to suppress food intake. NTS neurons that express preproglucagon (Ppg) (and which produce the food intake-suppressing PPG cleavage product, glucagon-like peptide-1 (GLP1)) represent a subpopulation of mouse LepRbNTS cells. Using Leprcre, Ppgcre, and Ppgflox mouse lines, along with designer receptors exclusively activated by designer drugs (DREADDs), we examined roles for Ppg in GLP1NTS and LepRbNTS cells for the control of food intake and energy balance. We found that the cre-dependent ablation of NTS Ppgflox early in development or in adult mice failed to alter energy balance, suggesting the importance of pathways independent of NTS GLP1 for the long-term control of food intake. Consistently, while activating GLP1NTS cells decreased food intake, LepRbNTS cells elicited larger and more durable effects. Furthermore, while the ablation of NTS Ppgflox blunted the ability of GLP1NTS neurons to suppress food intake during activation, it did not impact the suppression of food intake by LepRbNTS cells. While Ppg/GLP1-mediated neurotransmission plays a central role in the modest appetite-suppressing effects of GLP1NTS cells, additional pathways engaged by LepRbNTS cells dominate for the suppression of food intake.
Wenwen Cheng, Ermelinda Ndoka, Chelsea R. Hutch, Karen Roelofs, Andrew Mackinnon, Basma Khoury, Irwin J. Magrisso, Ki-Suk Kim, Christopher J. Rhodes, David P. Olson, Randy J. Seeley, Darleen A. Sandoval, Martin G. Myers Jr.
Carriers of the hydroxysteroid 17-β dehydrogenase 13 (HSD17B13) gene variant (rs72613567:TA) have a reduced risk of NASH and cirrhosis but not steatosis. We determined its effect on liver histology, lipidome, and transcriptome using ultra performance liquid chromatography-mass spectrometry and RNA-seq. In carriers and noncarriers of the gene variant, we also measured pathways of hepatic fatty acids (de novo lipogenesis [DNL] and adipose tissue lipolysis [ATL] using 2H2O and 2H-glycerol) and insulin sensitivity using 3H-glucose and euglycemic-hyperinsulinemic clamp) and plasma cytokines. Carriers and noncarriers had similar age, sex and BMI. Fibrosis was significantly less frequent while phospholipids, but not other lipids, were enriched in the liver in carriers compared with noncarriers. Expression of 274 genes was altered in carriers compared with noncarriers, consisting predominantly of downregulated inflammation-related gene sets. Plasma IL-6 concentrations were lower, but DNL, ATL and hepatic insulin sensitivity were similar between the groups. In conclusion, carriers of the HSD17B13 variant have decreased fibrosis and expression of inflammation-related genes but increased phospholipids in the liver. These changes are not secondary to steatosis, DNL, ATL, or hepatic insulin sensitivity. The increase in phospholipids and decrease in fibrosis are opposite to features of choline-deficient models of liver disease and suggest HSD17B13 as an attractive therapeutic target.
Panu K. Luukkonen, Taru Tukiainen, Anne Juuti, Henna Sammalkorpi, P.A. Nidhina Haridas, Onni Niemelä, Johanna Arola, Marju Orho-Melander, Antti Hakkarainen, Petri T. Kovanen, Om Dwivedi, Leif Groop, Leanne Hodson, Amalia Gastaldelli, Tuulia Hyötyläinen, Matej Orešič, Hannele Yki-Järvinen
SGLT2 inhibitors are beneficial in halting diabetic kidney disease; complete mechanisms is unknown. The epithelial to mesenchymal transition (EMT) is associated with Sirt3 suppression and aberrant glycolysis. Here, we hypothesized that the SGLT2 inhibitor restores normal kidney histology/function associated with the inhibition of aberrant glycolysis in diabetic kidneys. CD-1 mice with streptozotocin-induced diabetes displayed kidney fibrosis associated with the EMT at 4-months after diabetes induction. Empagliflozin intervention for one month restored all changes; adjustment of blood glucose by insulin did not. Empagliflozin normalized suppressed Sirt3 levels and aberrant glycolysis (characterized by hypoxia-inducible factor-1α accumulation, hexokinase 2 induction and pyruvate kinase isozyme M2 dimer formation) in diabetic kidneys. Empagliflozin also suppressed the accumulation of glycolysis byproducts in diabetic kidneys. Another SGLT2 inhibitor, canagliflozin, demonstrated similar in vivo effects. High-glucose media induced the EMT, which was associated with Sirt3 suppression and aberrant glycolysis induction, in the HK2 proximal tubule cell line; SGLT2 knockdown suppressed the EMT with restoration of all aberrant functions. SGLT2 suppression in tubular cells also inhibited the mesenchymal transition of neighboring endothelial cells. Taken together, SGLT2 inhibitors exhibit renoprotective potential that is partially dependent on the inhibition of glucose reabsorption and subsequent aberrant glycolysis in kidney tubules.
Jinpeng Li, Haijie Liu, Susumu Takagi, Kyoko Nitta, Munehiro Kitada, Swayam Prakash Srivastava, Yuta Takagaki, Keizo Kanasaki, Daisuke Koya
Severe obesity (SO) affects about 6% of youth in US, augmenting the risks for cardiovascular disease and Type 2 diabetes.Herein, we obtained paired omental (omVAT) and abdominal subcutaneous (SAT) adipose tissue biopsies from obese girls with SO, undergoing sleeve gastrectomy (SG), to test whether differences in cellular and transcriptomic profiles between omVAT and SAT depots affect insulin sensitivity differentially. Following weight loss, these analyses were repeated in a subgroup of subjects having a second SAT biopsy.We found that omVAT displayed smaller adipocytes compared to SAT, increased lipolysis through adipose triglyceride lipase (ATGL) phosphorylation, reduced inflammation and increased expression of browning/beige markers. Contrary to omVAT, SAT adipocyte diameter correlated with insulin resistance. Following SG, both weight and insulin sensitivity improved markedly in all subjects. SAT adipocytes size became smaller showing an increased lipolysis through perilipin-1 phosphorylation, decreased inflammation and increased expression in browning/beige markers.In summary, in adolescent girls with SO, both omVAT and SAT depots showed distinct cellular and transcriptomic profiles. Following weight loss, the SAT depot changed its cellular morphology and transcriptomic profiles into a more favorable one. These changes in the SAT depot may play a fundamental role in the resolution of insulin resistance.
Elena Tarabra, Jessica Nouws, Alla Vash-Margita, Geoffrey S. Nadzam, Rachel Goldberg-Gell, Michelle Van Name, Bridget Pierpont, James Knight, Gerald I. Shulman, Sonia Caprio
We hypothesized that skeletal muscle contraction produces a cellular stress signal triggering adipose tissue lipolysis to sustain fuel availability during exercise. The present study aimed at identifying novel exercise-regulated myokines, also known as exerkines, able to promote lipolysis.Human primary myotubes from lean healthy volunteers were submitted to electrical pulse stimulation (EPS) to mimic either acute intense or chronic moderate exercise. Conditioned media (CM) experiments with human adipocytes were performed. Conditioned media and human plasma samples were analyzed using unbiased proteomic and/or ELISA. Real-time qPCR was performed in cultured myotubes and muscle biopsy samples.CM from both acute intense and chronic moderate exercise increased basal lipolysis in human adipocytes (1.3 to 8 fold, p<0.001). Growth and Differentiation Factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was up-regulated in CM from both acute and chronic exercise-stimulated myotubes. We further show that physiological concentrations of recombinant GDF15 protein increase lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogates EPS CM-mediated lipolysis.We herein provide the first evidence that GDF15 is a novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.
Claire Laurens, Anisha Parmar, Enda Murphy, Deborah Carper, Benjamin Lair, Pauline Maes, Julie Vion, Nathalie Boulet, Coralie Fontaine, Marie-Adeline Marqués, Dominique Larrouy, Isabelle Harant, Claire Thalamas, Emilie Montastier, Sylvie Caspar-Bauguil, Virginie Bourlier, Geneviève Tavernier, Jean-Louis Grolleau, Anne Bouloumié, Dominique Langin, Nathalie Viguerie, Fabrice Bertile, Stéphane Blanc, Isabelle de Glisezinski, Donal J. O'Gorman, Cedric Moro
Patients with active acromegaly (ACRO) exhibit low hepatocellular lipids (HCL) despite pronounced insulin resistance (IR). This contrasts the strong association of IR with non-alcoholic fatty liver disease in the general population. Since low HCL in acromegaly might be caused by changes in oxidative substrate metabolism, we investigated mitochondrial activity and plasma metabolomics/lipidomics in active acromegaly. Fifteen ACRO and seventeen healthy controls (CON) matched for age, BMI, gender and body composition underwent 31P/1H-7T-MR-spectroscopy of the liver and skeletal muscle, as well as plasma metabolomic profiling and an oral glucose tolerance test. ACRO showed significant lower HCL but ATP-synthesis rate was significantly increased compared to CON. Furthermore, a decreased ratio of unsaturated to saturated intrahepatocellular fatty acids was found in ACRO. Within assessed plasma lipids, lipidomics, and metabolomics, decreased carnitine species also indicate increased mitochondrial activity. We therefore conclude that excess of growth hormone (GH) in humans counteracts hepatocellular lipid accumulation by increased hepatic ATP-synthesis. This is accompanied by a decreased ratio of unsaturated-to-saturated lipids in hepatocytes and by a metabolomic profile reflecting the increase in mitochondrial activity. Thus, these findings help to better understand GH-regulated antisteatotic pathways and provide a better insight into potential novel therapeutic targets for treating NAFLD.
Paul Fellinger, Peter Wolf, Lorenz Pfleger, Patrik Krumpolec, Martin Krssak, Kristaps Klavins, Stefan Wolfsberger, Alexander Micko, Patricia Carey, Bettina Gürtl, Greisa Vila, Wolfgang Raber, Clemens Fürnsinn, Thomas Scherer, Siegfried Trattnig, Alexandra Kautzky-Willer, Michael Krebs, Yvonne Winhofer
Background Salt-sensitive hypertension is often accompanied by insulin resistance in obese individuals, but the underlying mechanisms are obscure. Microvascular function is known to affect both salt-sensitivity of blood pressure and metabolic insulin sensitivity. We hypothesized that excessive salt intake increases blood pressure and decreases insulin-mediated glucose disposal, at least in part by impairing insulin-mediated muscle microvascular recruitment (IMMR). Methods In 20 lean and 20 abdominally obese individuals, we assessed mean arterial pressure (MAP; 24h ABPM), insulin-mediated whole body glucose disposal (M/I-value; hyperinsulinemic, euglycemic clamp technique), IMMR (contrast enhanced ultrasound), osmolyte and water balance, and excretion of mineralocorticoids, glucocorticoids, and amino and organic acids after a low and high salt diet during seven days in a randomized double-blind cross-over design. Results On a low, as compared to a high salt intake, MAP was lower, M/I-value was lower and IMMR was greater in both lean and abdominally obese individuals. In addition, Ln IMMR was inversely associated with MAP in lean participants on a low salt diet only. On a high salt diet, free water clearance decreased, and excretion of glucocorticoids and of amino acids involved in the urea cycle increased. Conclusion Our findings imply that hemodynamic and metabolic changes resulting from alterations in salt intake are not necessarily associated. Moreover, they are consistent with the concept that a high salt intake increases muscle glucose uptake as a response to high-salt-induced, glucocorticoid-drive muscle catabolism to stimulate urea production and thereby renal water conservation. Clinical Trial Registration Number: NCT02068781
Monica T.J. Schütten, Yvo H.A.M. Kusters, Alfons J.H.M. Houben, Hanneke E. C. Niessen, Jos op 't Roodt, Jean L.J. M. Scheijen, Marjo P. van de Waarenburg, Casper G. Schalkwijk, Peter W. de Leeuw, Coen D.A. Stehouwer
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