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Basic Research
Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition
Ho Gyun Lee, Il Hyeon Jung, Byong Seo Park, Hye Rim Yang, Kwang Kon Kim, Thai Hien Tu, Jung-Yong Yeh, Sewon Lee, Sunggu Yang, Byung Ju Lee, Jae Geun Kim, Il Seong Nam-Goong
Diabetes Metab J. 2023;47(6):784-795.   Published online August 23, 2023
DOI: https://doi.org/10.4093/dmj.2022.0261
  • 1,417 View
  • 149 Download
  • 2 Crossref
AbstractAbstract PDFPubReader   ePub   
Background
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are currently used to treat patients with diabetes. Previous studies have demonstrated that treatment with SGLT-2 inhibitors is accompanied by altered metabolic phenotypes. However, it has not been investigated whether the hypothalamic circuit participates in the development of the compensatory metabolic phenotypes triggered by the treatment with SGLT-2 inhibitors.
Methods
Mice were fed a standard diet or high-fat diet and treated with dapagliflozin, an SGLT-2 inhibitor. Food intake and energy expenditure were observed using indirect calorimetry system. The activity of hypothalamic neurons in response to dapagliflozin treatment was evaluated by immunohistochemistry with c-Fos antibody. Quantitative real-time polymerase chain reaction was performed to determine gene expression patterns in the hypothalamus of dapagliflozin-treated mice.
Results
Dapagliflozin-treated mice displayed enhanced food intake and reduced energy expenditure. Altered neuronal activities were observed in multiple hypothalamic nuclei in association with appetite regulation. Additionally, we found elevated immunosignals of agouti-related peptide neurons in the paraventricular nucleus of the hypothalamus.
Conclusion
This study suggests the functional involvement of the hypothalamus in the development of the compensatory metabolic phenotypes induced by SGLT-2 inhibitor treatment.

Citations

Citations to this article as recorded by  
  • Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition (Diabetes Metab J 2023;47:784-95)
    Jae Hyun Bae
    Diabetes & Metabolism Journal.2024; 48(1): 157.     CrossRef
  • Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition (Diabetes Metab J 2023;47:784-95)
    Ho Gyun Lee, Il Hyeon Jung, Byong Seo Park, Hye Rim Yang, Kwang Kon Kim, Thai Hien Tu, Jung-Yong Yeh, Sewon Lee, Sunggu Yang, Byung Ju Lee, Jae Geun Kim, Il Seong Nam-Goong
    Diabetes & Metabolism Journal.2024; 48(1): 159.     CrossRef
Drug/Regimen
Glucagon-Like Peptide-1 Receptor Agonist Differentially Affects Brain Activation in Response to Visual Food Cues in Lean and Obese Individuals with Type 2 Diabetes Mellitus
Jae Hyun Bae, Hyung Jin Choi, Kang Ik Kevin Cho, Lee Kyung Kim, Jun Soo Kwon, Young Min Cho
Diabetes Metab J. 2020;44(2):248-259.   Published online November 4, 2019
DOI: https://doi.org/10.4093/dmj.2019.0018
  • 7,388 View
  • 222 Download
  • 5 Web of Science
  • 6 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   
Background

To investigate the effects of a glucagon-like peptide-1 receptor agonist on functional brain activation in lean and obese individuals with type 2 diabetes mellitus (T2DM) in response to visual food cues.

Methods

In a randomized, single-blinded, crossover study, 15 lean and 14 obese individuals with T2DM were administered lixisenatide or normal saline subcutaneously with a 1-week washout period. We evaluated brain activation in response to pictures of high-calorie food, low-calorie food, and nonfood using functional magnetic resonance imaging and measured appetite and caloric intake in participants who were given access to an ad libitum buffet.

Results

Obese individuals with T2DM showed significantly greater activation of the hypothalamus, pineal gland, parietal cortex (high-calorie food vs. low-calorie food, P<0.05), orbitofrontal cortex (high-calorie food vs. nonfood, P<0.05), and visual cortex (food vs. nonfood, P<0.05) than lean individuals with T2DM. Lixisenatide injection significantly reduced the functional activation of the fusiform gyrus and lateral ventricle in obese individuals with T2DM compared with that in lean individuals with T2DM (nonfood vs. high-calorie food, P<0.05). In addition, in individuals who decreased their caloric intake after lixisenatide injection, there were significant interaction effects between group and treatment in the posterior cingulate, medial frontal cortex (high-calorie food vs. low-calorie food, P<0.05), hypothalamus, orbitofrontal cortex, and temporal lobe (food vs. nonfood, P<0.05).

Conclusion

Brain responses to visual food cues were different in lean and obese individuals with T2DM. In addition, acute administration of lixisenatide differentially affected functional brain activation in these individuals, especially in those who decreased their caloric intake after lixisenatide injection.

Citations

Citations to this article as recorded by  
  • Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition (Diabetes Metab J 2023;47:784-95)
    Jae Hyun Bae
    Diabetes & Metabolism Journal.2024; 48(1): 157.     CrossRef
  • Diabetes remission and relapse following an intensive metabolic intervention combining insulin glargine/lixisenatide, metformin and lifestyle approaches: Results of a randomised controlled trial
    Natalia McInnes, Stephanie Hall, Heather A. Lochnan, Stewart B. Harris, Zubin Punthakee, Ronald J. Sigal, Irene Hramiak, Mohammed Azharuddin, Joanne F. Liutkus, Jean‐François Yale, Farah Sultan, Ada Smith, Rose E. Otto, Diana Sherifali, Yan Yun Liu, Hertz
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  • Glucagon-like peptide-1 analog therapy in rare genetic diseases: monogenic obesity, monogenic diabetes, and spinal muscular atrophy
    Hussein Zaitoon, Ronit Lubetzky, Achiya Z. Amir, Hadar Moran-Lev, Liora Sagi, Michal Yacobi-Bach, Ophir Borger, Efrat Chorna, Yael Lebenthal, Avivit Brener
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  • What can functional brain imaging teach us about remission of type 2 diabetes?
    Dhruti Hirani, Shahd Alabdulkader, Alexander. D. Miras, Victoria Salem
    Diabetic Medicine.2023;[Epub]     CrossRef
  • Fasting oxyntomodulin, glicentin, and gastric inhibitory polypeptide levels are associated with activation of reward‐ and attention‐related brain centres in response to visual food cues in adults with obesity: A cross‐sectional functional MRI study
    Nikolaos Perakakis, Olivia M. Farr, Christos S. Mantzoros
    Diabetes, Obesity and Metabolism.2021; 23(5): 1202.     CrossRef
  • Aberrant Brain Functional Connectivity Strength and Effective Connectivity in Patients with Type 2 Diabetes Mellitus
    Xi Guo, Su Wang, Yu-Chen Chen, Heng-Le Wei, Gang-Ping Zhou, Yu-Sheng Yu, Xindao Yin, Kun Wang, Hong Zhang, Eusebio Chiefari
    Journal of Diabetes Research.2021; 2021: 1.     CrossRef
Review
Molecular Mechanisms of Appetite Regulation
Ji Hee Yu, Min-Seon Kim
Diabetes Metab J. 2012;36(6):391-398.   Published online December 12, 2012
DOI: https://doi.org/10.4093/dmj.2012.36.6.391
  • 8,979 View
  • 215 Download
  • 80 Crossref
AbstractAbstract PDFPubReader   

The prevalence of obesity has been rapidly increasing worldwide over the last several decades and has become a major health problem in developed countries. The brain, especially the hypothalamus, plays a key role in the control of food intake by sensing metabolic signals from peripheral organs and modulating feeding behaviors. To accomplish these important roles, the hypothalamus communicates with other brain areas such as the brainstem and reward-related limbic pathways. The adipocyte-derived hormone leptin and pancreatic β-cell-derived insulin inform adiposity to the hypothalamus. Gut hormones such as cholecystokinin, peptide YY, pancreatic polypeptide, glucagon-like peptide 1, and oxyntomodulin transfer satiety signals to the brain and ghrelin relays hunger signals. The endocannabinoid system and nutrients are also involved in the physiological regulation of food intake. In this article, we briefly review physiological mechanisms of appetite regulation.

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Original Articles
Intracerebroventricular Injection of Metformin Induces Anorexia in Rats
Chang Koo Lee, Yoon Jung Choi, So Young Park, Jong Yeon Kim, Kyu Chang Won, Yong Woon Kim
Diabetes Metab J. 2012;36(4):293-299.   Published online August 20, 2012
DOI: https://doi.org/10.4093/dmj.2012.36.4.293
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AbstractAbstract PDFPubReader   
Background

Metformin, an oral biguanide insulin-sensitizing agent, is well known to decrease appetite. Although there is evidence that metformin could affect the brain directly, the exact mechanism is not yet known.

Methods

To evaluate whether metformin induces anorexia via the hypothalamus, various concentrations of metformin were injected into the lateral ventricle of rats through a chronically implanted catheter and food intake was measured for 24 hours. The hypothalamic neuropeptides associated with regulation of food intake were also analyzed following 1 hour of intracerebroventricular (ICV) injections of metformin.

Results

An ICV injection of metformin decreased food intake in a dose-dependent manner in unrestrained conscious rats. Hypothalamic phosphorylated AMP-activated protein kinase (pAMPK) increased by 3 µg with metformin treatment, but there was no further increase in pAMPK with increases in metformin dosage. The hypothalamic phosphorylated signal transducer and activator of transcription 3 (pSTAT3) increased by 3 µg with metformin treatment, but, there was no further increase in pSTAT3 level following increases of metformin dosage. Hypothalamic proopiomelanocortin was elevated with metformin treatment, while neuropeptide Y was not significantly changed.

Conclusion

Our results suggest that metformin induces anorexia via direct action in the hypothalamus and the increase in pSTAT3, at least in part, is involved in the process. However, hypothalamic pAMPK appears not to contribute to metformin-induced appetite reduction in normal rats. Further studies exploring new pathways connecting metformin and feeding regulation are needed.

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ATP-Sensitive Potassium Channel-Deficient Mice Show Hyperphagia but Are Resistant to Obesity
Yeul Bum Park, Yun Jung Choi, So Young Park, Jong Yeon Kim, Seong Ho Kim, Dae Kyu Song, Kyu Chang Won, Yong Woon Kim
Diabetes Metab J. 2011;35(3):219-225.   Published online June 30, 2011
DOI: https://doi.org/10.4093/dmj.2011.35.3.219
  • 3,538 View
  • 31 Download
  • 14 Crossref
AbstractAbstract PDFPubReader   
Background

The hypothalamus, the center for body weight regulation, can sense changes in blood glucose level based on ATP-sensitive potassium (KATP) channels in the hypothalamic neurons. We hypothesized that a lack of glucose sensing in the hypothalamus affects the regulations of appetite and body weight.

Methods

To evaluate this hypothesis, the responses to glucose loading and high fat feeding for eight weeks were compared in Kir6.2 knock-out (KO) mice and control C57BL/6 mice, because Kir6.2 is a key component of the KATP channel.

Results

The hypothalamic neuropeptide Y (NPY) analyzed one hour after glucose injection was suppressed in C57BL/6 mice, but not in Kir6.2 KO mice, suggesting a blunted hypothalamic response to glucose in Kir6.2 KO mice. The hypothalamic NPY expression at a fed state was elevated in Kir6.2 KO mice and was accompanied with hyperphagia. However, the retroperitoneal fat mass was markedly decreased in Kir6.2 KO mice compared to that in C57BL/6 mice. Moreover, the body weight and visceral fat following eight weeks of high fat feeding in Kir6.2 KO mice were not significantly different from those in control diet-fed Kir6.2 KO mice, while body weight and visceral fat mass were elevated due to high fat feeding in C57BL/6 mice.

Conclusion

These results suggested that Kir6.2 KO mice showed a blunted hypothalamic response to glucose loading and elevated hypothalamic NPY expression accompanied with hyperphagia, while visceral fat mass was decreased, suggesting resistance to diet-induced obesity. Further study is needed to explain this phenomenon.

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Diabetes Metab J : Diabetes & Metabolism Journal