A glucagon analogue decreases body weight in mice via signalling in the liver

AbstractGlucagon receptor agonists show promise as components of next generation metabolic syndrome pharmacotherapies. However, the biology of glucagon action is complex, controversial, and likely context dependent. As such, a better understanding of chronic glucagon receptor (GCGR) agonism is essential to identify and mitigate potential clinical side-effects. Herein we present a novel, long-acting glucagon analogue (GCG104) with high receptor-specificity and potent in vivo action. It has allowed us to make two important observations about the biology of sustained GCGR agonism. First, it causes weight loss in mice by direct receptor signalling at the level of the liver. Second, subtle changes in GCG104-sensitivity, possibly due to interindividual variation, may be sufficient to alter its effects on metabolic parameters. Together, these findings confirm the liver as a principal target for glucagon-mediated weight loss and provide new insights into the biology of glucagon analogues.

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1965-P: Glucagon Receptor Agonism Stimulates Body Weight Loss in Antibiotic Treatment in Obese Mice

Diabetes ◽

10.2337/db19-1965-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 1965-P

Author(s):

TEAYOUN KIM ◽

JESSICA P. ANTIPENKO ◽

SHELLY NASON ◽

NATALIE PRESEDO ◽

WILLIAM J. VAN DER POL ◽

...

Keyword(s):

Weight Loss ◽

Body Weight ◽

Antibiotic Treatment ◽

Body Weight Loss ◽

Obese Mice ◽

Glucagon Receptor

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European Guidelines for Obesity Management in Adults with a Very Low-Calorie Ketogenic Diet: A Systematic Review and Meta-Analysis

Obesity Facts ◽

10.1159/000515381 ◽

2021 ◽

Vol 14 (2) ◽

pp. 222-245

Author(s):

Giovanna Muscogiuri ◽

Marwan El Ghoch ◽

Annamaria Colao ◽

Maria Hassapidou ◽

Volkan Yumuk ◽

...

Keyword(s):

Systematic Review ◽

Weight Loss ◽

Body Composition ◽

Body Weight ◽

Side Effects ◽

Ketogenic Diet ◽

Meta Analysis ◽

Dietary Treatment ◽

Obesity Management ◽

Weight Loss Interventions

Background: The very low-calorie ketogenic diet (VLCKD) has been recently proposed as an appealing nutritional strategy for obesity management. The VLCKD is characterized by a low carbohydrate content (<50 g/day), 1–1.5 g of protein/kg of ideal body weight, 15–30 g of fat/day, and a daily intake of about 500–800 calories. Objectives: The aim of the current document is to suggest a common protocol for VLCKD and to summarize the existing literature on its efficacy in weight management and weight-related comorbidities, as well as the possible side effects. Methods: This document has been prepared in adherence with Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Literature searches, study selection, methodology development, and quality appraisal were performed independently by 2 authors and the data were collated by means of a meta-analysis and narrative synthesis. Results: Of the 645 articles retrieved, 15 studies met the inclusion criteria and were reviewed, revealing 4 main findings. First, the VLCKD was shown to result in a significant weight loss in the short, intermediate, and long terms and improvement in body composition parameters as well as glycemic and lipid profiles. Second, when compared with other weight loss interventions of the same duration, the VLCKD showed a major effect on reduction of body weight, fat mass, waist circumference, total cholesterol and triglyceridemia as well as improved insulin resistance. Third, although the VLCKD also resulted in a significant reduction of glycemia, HbA1c, and LDL cholesterol, these changes were similar to those obtained with other weight loss interventions. Finally, the VLCKD can be considered a safe nutritional approach under a health professional’s supervision since the most common side effects are usually clinically mild and easily to manage and recovery is often spontaneous. Conclusions: The VLCKD can be recommended as an effective dietary treatment for individuals with obesity after considering potential contra-indications and keeping in mind that any dietary treatment has to be personalized. Prospero Registry: The assessment of the efficacy of VLCKD on body weight, body composition, glycemic and lipid parameters in overweight and obese subjects: a meta-analysis (CRD42020205189).

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Attitudes about Antidepressants: Influence of Information about Weight-Related Side Effects

Perceptual and Motor Skills ◽

10.2466/pms.2000.90.2.453 ◽

2000 ◽

Vol 90 (2) ◽

pp. 453-456 ◽

Cited By ~ 5

Author(s):

Thomas F. Cash ◽

Melissa A. Brown

Keyword(s):

Weight Loss ◽

Body Image ◽

Body Weight ◽

Weight Gain ◽

Side Effects ◽

College Women ◽

Antidepressant Drugs ◽

Antidepressant Medications ◽

Body Image Ideals ◽

Clinical Populations

Antidepressant drugs are frequently prescribed for women and have various side effects, including potential effects on body weight. This experiment examined the effects of information about the weight-related side effects of antidepressants on women's attitudes toward the drugs. 60 college women were randomly assigned to read about one of two drugs, fluoxetine (Prozac) or Imipramine (Tofranil). Participants were either told or not told about veridical weight-related side effects, namely, weight loss for Prozac and weight gain for Tofranil. As hypothesized, weight-gain information lowered the personal acceptability of Tofranil, and weight-loss information enhanced the acceptability of Prozac. Although research with clinical populations is required, undergraduate women's decisions about the use of antidepressant medications may be influenced by societal body-image ideals.

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Leptin causes body weight loss in the absence of in vivo activities typical of cytokines of the IL-6 family

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.275.3.r913 ◽

1998 ◽

Vol 275 (3) ◽

pp. R913-R919 ◽

Cited By ~ 3

Author(s):

Davide Agnello ◽

Cristina Meazza ◽

Christopher G. Rowan ◽

Pia Villa ◽

Pietro Ghezzi ◽

...

Keyword(s):

Weight Loss ◽

Body Weight ◽

Body Weight Loss ◽

Peripheral Blood Cell ◽

Serum Corticosterone ◽

Amyloid A ◽

Cell Counts ◽

Control Body ◽

The One

To investigate if leptin shares in vivo activities with interleukin (IL)-6 family cytokines, it was tested in normal mice for the ability, after a single injection, to induce the acute-phase protein serum amyloid A, to potentiate the induction by IL-1 of serum corticosterone and IL-6, and to inhibit the induction by lipopolysaccharide of serum tumor necrosis factor and, after seven daily injections, to cause body weight loss and to change peripheral blood cell counts. At a 0.5 mg/kg dose, leptin caused body weight loss but did not show any of the other activities above. At a dose of 5 mg/kg, which also caused body weight loss, leptin potentiated the induction by IL-1 of serum corticosterone and IL-6 but did not show any other activity. In addition to causing body weight loss, leptin shows only some of the in vivo activities typical of IL-6 family cytokines and only if used at a dose that exceeds the one sufficient to affect body weight. In vivo, leptin seems to chiefly control body weight and not inflammatory or hematopoietic processes.

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OR28-5 Bile Acid Sequestration Accelerates Glucagon Receptor-Mediated Body Weight Loss in Obese Mice

Journal of the Endocrine Society ◽

10.1210/js.2019-or28-5 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Teayoun Kim ◽

Shelly Nason ◽

Jessica Antipenko ◽

Natalie Presedo ◽

Brian Finan ◽

...

Keyword(s):

Weight Loss ◽

Body Weight ◽

Bile Acid ◽

Body Weight Loss ◽

Obese Mice ◽

Glucagon Receptor

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Effects of Cotadutide on Metabolic and Hepatic Parameters in Adults with Overweight or Obesity and Type 2 Diabetes Mellitus: A 54-Week Randomized Phase 2b Study

10.2337/figshare.14272955.v1 ◽

2021 ◽

Author(s):

Rajaa Nahra ◽

Tao Wang ◽

Kishore M. Gadde ◽

Jan Oscarsson ◽

Michael Stumvoll ◽

...

Keyword(s):

Type 2 Diabetes ◽

Weight Loss ◽

Body Weight ◽

Ad Hoc ◽

Open Label ◽

Double Blind ◽

Glucagon Receptor ◽

Nonalcoholic Fatty Liver ◽

Design And Methods

<a>Objective: </a>Cotadutide, a <a>dual GLP-1 and glucagon receptor agonist</a>, is under development for nonalcoholic steatohepatitis (NASH) and type 2 diabetes. The effects of cotadutide on hepatic and metabolic parameters were evaluated in participants with overweight/obesity and type 2 diabetes. Research Design and Methods: In this phase 2b study, 834 adults with BMI ≥25kg/m2 and type 2 diabetes inadequately controlled with metformin (glycated hemoglobin A1c [HbA1c] of 7.0%─10.5% [53─91 mmol/mol]) were randomized to double-blind cotadutide 100µg (n=100), 200µg (n=256), or 300µg (n=256), placebo (n=110), or open-label liraglutide 1.8mg (n=110), all administered subcutaneously (NCT03235050). Coprimary endpoints were changes in HbA1c and body weight at week 14. The originally randomized interventions were continued to week 54. Liver damage biomarkers and liver fibrosis algorithms were assessed. Results: Cotadutide significantly decreased HbA1c and body weight at weeks 14 and 54 versus placebo (all P<0.001). Improvements in lipid profile, aspartate aminotransferase and alanine aminotransferase levels, <a>PRO-C3 level, fibrosis-4 index</a>, and <a>nonalcoholic fatty liver disease fibrosis score</a> were observed with cotadutide 300µg versus placebo, but not with liraglutide. Weight loss with cotadutide 200µg was similar to liraglutide 1.8mg, and greater with cotadutide 300µg versus liraglutide 1.8mg. <a>The most common adverse events with cotadutide (nausea, 35%; vomiting, 17%) decreased over time. </a> Conclusions: Cotadutide treatment for 54 weeks improved glycemic control and weight loss in participants with overweight/obesity and type 2 diabetes. Ad hoc analyses demonstrated improvements in hepatic parameters and support further evaluation of cotadutide in NASH.

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Onset of Ulcerative Colitis in a Patient with Nonalcoholic Fatty Liver Disease (NAFLD): Dramatic Effect of Plant-based Diet for NAFLD

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz208 ◽

2019 ◽

Vol 25 (11) ◽

pp. e146-e147 ◽

Cited By ~ 2

Author(s):

Mitsuro Chiba ◽

Kunio Nakane ◽

Hitoshi Abe ◽

Masafumi Komatsu ◽

Haruhiko Tozawa

Keyword(s):

Ulcerative Colitis ◽

Metabolic Syndrome ◽

Weight Loss ◽

Body Weight ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Nonalcoholic Fatty Liver ◽

Normal Ranges

Abstract Nonalcoholic fatty liver disease (NAFLD) develops in ulcerative colitis (UC) and Crohn’s disease. However, there is scarce reporting on the onset of UC in patients with NAFLD. A 44-year-old man was diagnosed with UC and referred to us in 2019. His height was 166.0 cm, and body weight was 86.3 kg. The waist circumference was 93.7 cm (normal range <85) and triglyceride was 751 mg/dL. These findings, in addition to hypertension, resulted in a diagnosis of metabolic syndrome. HbA1c was normal. Ultrasonography disclosed severe fatty liver. Nonalcoholic fatty liver disease was diagnosed. He underwent 12 days of educational hospitalization for UC. A lacto-ovo-semi-vegetarian diet (1400 kcal/day), a kind of plant-based diet (PBD), was provided. He lost 4 kg, which was 4.6% of his base body weight. Triglyceride and total cholesterol decreased to the normal ranges. Transaminases and γ-glutamyl transpeptidase also decreased. His body weight decreased further after discharge. Follow-up ultrasonography indicated an improvement in hepatic enlargement. The shear wave velocity decreased from 1.11 to 0.88 m/s. His soft stool became normal stool by 2 months after discharge. Records of his health checkups revealed the presence of metabolic syndrome and abnormal liver function tests already in 2015. Thus, it was concluded that UC developed in a patient with NAFLD in this case. Plant-based diet has already been shown to be effective in inflammatory bowel disease (IBD). In the present case, NAFLD parameters were dramatically improved by PBD. Whether the improvement was due to weight loss per se or due to weight loss with PBD is to be clarified.

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Prolonged intake of desloratadine: mesenteric lymphatic vessel dysfunction and development of obesity/metabolic syndrome

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00321.2018 ◽

2019 ◽

Vol 316 (1) ◽

pp. G217-G227 ◽

Cited By ~ 5

Author(s):

Olga Y. Gasheva ◽

Irina Tsoy Nizamutdinova ◽

Laura Hargrove ◽

Cassidy Gobbell ◽

Maria Troyanova-Wood ◽

...

Keyword(s):

Metabolic Syndrome ◽

Body Weight ◽

Weight Gain ◽

Side Effects ◽

Lymphatic Vessel ◽

Fasting Blood Glucose ◽

Lymphatic Vessels ◽

The United States ◽

Lymph Flow ◽

The Body

This study aimed to establish mechanistic links between the prolonged intake of desloratadine, a common H1 receptor blocker (i.e., antihistamine), and development of obesity and metabolic syndrome. Male Sprague-Dawley rats were treated for 16 wk with desloratadine. We analyzed the dynamics of body weight gain, tissue fat accumulation/density, contractility of isolated mesenteric lymphatic vessels, and levels of blood lipids, glucose, and insulin, together with parameters of liver function. Prolonged intake of desloratadine induced development of an obesity-like phenotype and signs of metabolic syndrome. These alterations in the body included excessive weight gain, increased density of abdominal subcutaneous fat and intracapsular brown fat, high blood triglycerides with an indication of their rerouting toward portal blood, high HDL, high fasting blood glucose with normal fasting and nonfasting insulin levels (insulin resistance), high liver/body weight ratio, and liver steatosis (fatty liver). These changes were associated with dysfunction of mesenteric lymphatic vessels, specifically high lymphatic tone and resistance to flow together with diminished tonic and abolished phasic responses to increases in flow, (i.e., greatly diminished adaptive reserves to respond to postprandial increases in lymph flow). The role of nitric oxide in this flow-dependent adaptation was abolished, with remnants of these responses controlled by lymphatic vessel-derived histamine. Our current data, considered together with reports in the literature, support the notion that millions of the United States population are highly likely affected by underevaluated, lymphatic-related side effects of antihistamines and may develop obesity and metabolic syndrome due to the prolonged intake of this medication. NEW & NOTEWORTHY Prolonged intake of desloratadine induced development of obesity and metabolic syndrome associated with dysfunction of mesenteric lymphatic vessels, high lymphatic tone, and resistance to flow together with greatly diminished adaptive reserves to respond to postprandial increases in lymph flow. Data support the notion that millions of the USA population are highly likely affected by underevaluated, lymphatic-related side effects of antihistamines and may develop obesity and metabolic syndrome due to the prolonged intake of this medication.

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Effects of a 3-Week In-Hospital Body Weight Reduction Program on Cardiovascular Risk Factors, Muscle Performance, and Fatigue: A Retrospective Study in a Population of Obese Adults with or without Metabolic Syndrome

Nutrients ◽

10.3390/nu12051495 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1495 ◽

Cited By ~ 1

Author(s):

Antonello E. Rigamonti ◽

Sabrina Cicolini ◽

Diana Caroli ◽

Alessandra De Col ◽

Massimo Scacchi ◽

...

Keyword(s):

Metabolic Syndrome ◽

Weight Loss ◽

Body Weight ◽

Weight Reduction ◽

Hdl Cholesterol ◽

Muscle Performance ◽

Weight Reduction Program ◽

Body Weight Reduction ◽

Reduction Program ◽

Obese Subjects

Background. In clinical practice, there is the diffuse conviction that obese subjects with metabolic syndrome may be more difficult to treat. Objectives and Methods. The aim of the present study was that to investigate the effectiveness of a 3-week in-hospital body weight reduction program (BWRP) in a large population of obese subjects with and without metabolic syndrome (n = 1922; 222 men and 1700 women, age range 18–83 yr). Outcomes such as body mass index (BMI), total (TOT) and HDL cholesterol, systolic and diastolic blood pressures (SBP and DBP, respectively), coronary heart disease (CHD) score, fatigue severity score (FSS), and stair climbing test (SCT) time were evaluated before and after the intervention (Δ). A sex-, BMI-, and age-related stratification of the obese population with or without metabolic syndrome was applied. Results. When compared to obese subjects without metabolic syndrome, at the basal conditions, obese subjects had a poorer cardiometabolic profile, as demonstrated by higher triglycerides, TOT-cholesterol, DBP, SBP, and CHD score, and a more compromised muscle performance (evaluated by SCT), associated with more perception of fatigue (measured by FSS). Nevertheless, obese subjects with metabolic syndrome obtained more benefits from BWRP than those without metabolic syndrome for some outcomes (i.e., ΔTOT-cholesterol, ΔSBP, and ΔCHD score). Despite these differences, the BWRP-induced weight loss was similar between the two groups (i.e., ΔBMI) as well as the gain of muscle performance (i.e., ΔSCT) and the reduction of fatigue (i.e., ΔFSS). Interestingly, the potentially deleterious fall in HDL-cholesterol levels after BWRP was less evident in obese subjects with metabolic syndrome than those without metabolic syndrome. When pooling all data, the ΔCHD score was associated with age, sex, and metabolic syndrome. The remaining outcomes, such as ΔBMI, ΔFSS, and ΔSCT time, were associated with sex and age but not with metabolic syndrome. Finally, ΔBMI was positively correlated with ΔCHD score, ΔFSS, and ΔSCT time in both obese subjects without metabolic syndrome and obese subjects with metabolic syndrome. Conclusions. When comparing obese subjects undergoing a BWRP, metabolic syndrome is not a negative predictive factor affecting the effectiveness of this intervention in terms of weight loss, muscle performance, and psychological well-being.

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Effect of the Mediterranean diet with and without weight loss on surrogate markers of cholesterol homeostasis in men with the metabolic syndrome

British Journal Of Nutrition ◽

10.1017/s0007114511003436 ◽

2011 ◽

Vol 107 (5) ◽

pp. 705-711 ◽

Cited By ~ 43

Author(s):

Caroline Richard ◽

Patrick Couture ◽

Sophie Desroches ◽

Suzanne Benjannet ◽

Nabil G. Seidah ◽

...

Keyword(s):

Metabolic Syndrome ◽

Weight Loss ◽

Body Weight ◽

Control Diet ◽

Cholesterol Absorption ◽

Energy Restriction ◽

Surrogate Markers ◽

The Metabolic Syndrome ◽

The Mediterranean ◽

The Impact

The mechanisms implicated in the LDL-cholesterol (LDL-C)-lowering effects of the Mediterranean-type diet (MedDiet) are unknown. The present study assessed the impact of the MedDiet consumed under controlled feeding conditions, with and without weight loss, on surrogate markers of cholesterol absorption, synthesis and clearance using plasma phytosterols, lathosterol and proprotein convertase subtilisin/kexin-9 (PCSK9) concentrations, respectively, in men with the metabolic syndrome. The subjects' diet (n19, 24–62 years) was first standardised to a baseline North American control diet (5 weeks) followed by a MedDiet (5 weeks), both under weight-maintaining isoenergetic feeding conditions. The participants then underwent a 20-week free-living energy restriction period (10 (sd3) % reduction in body weight,P < 0·01), followed by the consumption of the MedDiet (5 weeks) under controlled isoenergetic feeding conditions. The LDL-C-lowering effect of the MedDiet in the absence of weight loss ( − 9·9 %) was accompanied by significant reductions in plasma PCSK9 concentrations ( − 11·7 %,P < 0·01) and in the phytosterol:cholesterol ratio ( − 9·7 %,P < 0·01) compared with the control diet. The addition of weight loss to the MedDiet had no further impact on plasma LDL-C concentrations and on these surrogate markers of LDL clearance and cholesterol absorption. The present results suggest that the MedDiet reduces plasma LDL-C concentrations primarily by increasing LDL clearance and reducing cholesterol absorption, with no synergistic effect of body weight loss in this process.

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