simple-continuous-glucose-monitoring-in-freely-moving-mice

Simple Continuous Glucose Monitoring in Freely Moving Mice

Mice are a common model organism used to study metabolic diseases such as diabetes mellitus. Glucose levels are typically measured by tail-bleeding, which ...

The Hebrew University-Hadassah Medical School

Bariatric surgery dramatically improves glycemic control, yet the underlying molecular mechanisms remain controversial because of confounding weight loss. We performed sleeve gastrectomy (SG) on obese and diabetic leptin receptor-deficient mice (/). One week postsurgery, mice weighed 5% less and displayed improved glycemia compared with sham-operated controls, and islets from SG mice displayed reduced expression of diabetes markers. One month postsurgery SG mice weighed more than preoperatively but remained near-euglycemic and displayed reduced hepatic lipid droplets. Pair feeding of SG and sham / mice showed that surgery rather than weight loss was responsible for reduced glycemia after SG. Although insulin secretion profiles from islets of sham and SG mice were indistinguishable, clamp studies revealed that SG causes a dramatic improvement in muscle and hepatic insulin sensitivity accompanied by hepatic regulation of hepatocyte nuclear factor-α and peroxisome proliferator-activated receptor-α targets. We conclude that long-term weight loss after SG requires leptin signaling. Nevertheless, SG elicits a remarkable improvement in glycemia through insulin sensitization independent of reduced feeding and weight loss.

Sleeve Gastrectomy Improves Glycemia Independent of Weight Loss by Restoring Hepatic Insulin Sensitivity.

The effectiveness of Roux-en-Y gastric bypass (RYGB) against obesity and its comorbidities has generated excitement about developing new, less invasive treatments that use the same molecular mechanisms. Although controversial, RYGB-induced improvement of metabolic function may not depend entirely upon weight loss. To elucidate the differences between RYGB and dieting, we studied several individual organ molecular responses and generated an integrative, interorgan view of organismal physiology. We also compared murine and human molecular signatures. We show that, although dieting and RYGB can bring about the same degree of weight loss, post-RYGB physiology is very different. RYGB induces distinct, organ-specific adaptations in a temporal pattern that is characterized by energetically demanding processes, which may be coordinated by HIF1a activation and the systemic repression of growth hormone receptor signaling. Many of these responses are conserved in rodents and humans and may contribute to the remarkable ability of surgery to induce and sustain metabolic improvement.

Time-Dependent Molecular Responses Differ between Gastric Bypass and Dieting but Are Conserved Across Species.

Acute MI induces leptin expression in the heart, however the role of myocardial leptin in cardiac ischemia and reperfusion (IR) remains unknown. To shed light on the effects of elevated levels of leptin in the myocardium, we overexpressed cardiac leptin and assessed local remodeling and myocardial function in this context.

Cardiac leptin overexpression in the context of acute MI and reperfusion potentiates myocardial remodeling and left ventricular dysfunction.

Obesity is a global epidemic that causes morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-G signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. In addition, our findings indicate that calcium (Ca) is required for agonist, but not antagonist, efficacy. These results fill a gap in the understanding of MC4R activation and could guide the design of future weight-management drugs.

Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.

Bariatric operations induce weight loss, which is associated with an improvement in hepatic steatosis and a reduction in hepatic glucose production. It is not clear whether these outcomes are entirely due to weight loss, or whether the new anatomy imposed by the surgery contributes to the improvement in the metabolic function of the liver. We performed vertical sleeve gastrectomy (VSG) on obese mice provided with a high-fat high-sucrose diet and compared them to diet and weight-matched sham-operated mice (WMS). At 40 days after surgery, VSG-operated mice displayed less hepatic steatosis compared with WMS. By measuring the fasting glucose and insulin levels in the blood vessels feeding and draining the liver, we showed directly that hepatic glucose production was suppressed after VSG. Insulin levels were elevated in the portal vein, and hepatic insulin clearance was elevated in VSG-operated mice. The hepatic expression of genes associated with insulin clearance was upregulated. We repeated the experiment in lean mice and observed that portal insulin and glucagon are elevated, but only insulin clearance is increased in VSG-operated mice. In conclusion, direct measurement of glucose and insulin in the blood entering and leaving the liver shows that VSG affects glucose and insulin metabolism through mechanisms independent of weight loss and diet.

Sleeve Gastrectomy Suppresses Hepatic Glucose Production and Increases Hepatic Insulin Clearance Independent of Weight Loss.

The incidences of obesity and attention-deficit/hyperactivity disorder (ADHD) have increased in parallel over recent decades. We assessed the association between obesity and ADHD in a national sample of adolescents.

Attention-Deficit/Hyperactivity Disorder and Obesity: A National Study of 1.1 Million Israeli Adolescents.

Until recently, communication between neighboring cells in islets of Langerhans was overlooked by genomic technologies, which require rigorous tissue dissociation into single cells.

Physically interacting beta-delta pairs in the regenerating pancreas revealed by single-cell sequencing.

We report the long-term response to bariatric surgery in a singular family of four adolescents with severe obesity (41-82 kg/m), homozygous for the C271R loss-of-function mutation in the melanocortin 4 receptor (MC4R), and three adults heterozygous for the same mutation. All patients had similar sociodemographic backgrounds and were followed for an average of 7 years. Three of the four homozygous patients regained their full weight (42-77 kg/m), while the fourth lost weight but remained obese with a body mass index of 60 kg/m. Weight regain was associated with relapse of most comorbidities, yet hyperglycemia did not relapse or was delayed. A1c levels were reduced in homozygous and heterozygous patients. The long-term follow-up data on this very unique genetic setting show that weight loss and amelioration of obesity following bariatric surgery require active MC4R signaling, while the improvement in glycemia is in part independent of weight loss. The study validates animal models and demonstrates the importance of biological signaling in the regulation of weight, even after bariatric surgery.

Article	Year
Sleeve Gastrectomy Improves Glycemia Independent of Weight Loss by Restoring Hepatic Insulin Sensitivity. Diabetes\| PubMed ID: 29475831	2018
Time-Dependent Molecular Responses Differ between Gastric Bypass and Dieting but Are Conserved Across Species. Cell metabolism\| PubMed ID: 30043755	2018
Cardiac leptin overexpression in the context of acute MI and reperfusion potentiates myocardial remodeling and left ventricular dysfunction. PloS one\| PubMed ID: 30312306	2018
Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling. Science (New York, N.Y.)\| PubMed ID: 33858992	2021
Sleeve Gastrectomy Suppresses Hepatic Glucose Production and Increases Hepatic Insulin Clearance Independent of Weight Loss. Diabetes\| PubMed ID: 34341005	2021
Attention-Deficit/Hyperactivity Disorder and Obesity: A National Study of 1.1 Million Israeli Adolescents. The Journal of clinical endocrinology and metabolism\| PubMed ID: 34850003	2022
Physically interacting beta-delta pairs in the regenerating pancreas revealed by single-cell sequencing. Molecular metabolism\| PubMed ID: 35240340	2022
The Obesogenic and Glycemic Effect of Bariatric Surgery in a Family with a Melanocortin 4 Receptor Loss-of-Function Mutation. Metabolites\| PubMed ID: 35629934	2022

Danny Ben-Zvi

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