Glucagon-Like Peptide-1 Agonist Exendin-4 Leads to Reduction of Weight and Caloric Intake in a Rat Model of Hypothalamic Obesity

Elfers, Clinton; Simmons, Jill H.; Roth, Christian

doi:10.1159/000338464

Cited by 13 publications

(13 citation statements)

References 84 publications

(64 reference statements)

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“…Intraperitoneal injection of GLP‐1RA liraglutide and exendin‐4 also reduced food intake in non‐diabetic rats. In addition, subcutaneous injections of liraglutide significantly reduced the food intake and bodyweight in diabetic ob / ob and db / db mice, as well as in obese candy‐fed rats, obese mini‐pigs and obese rats carrying hypothalamic lesions. It was also shown that GLP‐1 or GLP‐1RA liraglutide infusion reduced food intake and reduced gastric emptying in healthy volunteers, patients with type 1 diabetes and patients with type 2 diabetes.…”

Section: Diabetes‐related Comorbiditiesmentioning

confidence: 93%

Glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1: Incretin actions beyond the pancreas

Seino

Yabe

2013

J of Diabetes Invest

225

186

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Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the two primary incretin hormones secreted from the intestine on ingestion of various nutrients to stimulate insulin secretion from pancreatic b-cells glucose-dependently. GIP and GLP-1 undergo degradation by dipeptidyl peptidase-4 (DPP-4), and rapidly lose their biological activities. The actions of GIP and GLP-1 are mediated by their specific receptors, the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R), which are expressed in pancreatic b-cells, as well as in various tissues and organs. A series of investigations using mice lacking GIPR and/or GLP-1R, as well as mice lacking DPP-4, showed involvement of GIP and GLP-1 in divergent biological activities, some of which could have implications for preventing diabetes-related microvascular complications (e.g., retinopathy, nephropathy and neuropathy) and macrovascular complications (e.g., coronary artery disease, peripheral artery disease and cerebrovascular disease), as well as diabetes-related comorbidity (e.g., obesity, non-alcoholic fatty liver disease, bone fracture and cognitive dysfunction). Furthermore, recent studies using incretin-based drugs, such as GLP-1 receptor agonists, which stably activate GLP-1R signaling, and DPP-4 inhibitors, which enhance both GLP-1R and GIPR signaling, showed that GLP-1 and GIP exert effects possibly linked to prevention or treatment of diabetes-related complications and comorbidities independently of hyperglycemia. We review recent findings on the extrapancreatic effects of GIP and GLP-1 on the heart, brain, kidney, eye and nerves, as well as in the liver, fat and several organs from the perspective of diabetes-related complications and comorbidities. (J Diabetes Invest,

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Section: Diabetes‐related Comorbiditiesmentioning

confidence: 93%

Glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1: Incretin actions beyond the pancreas

Seino

Yabe

2013

J of Diabetes Invest

225

186

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“…Recently, the CMHL rat model was used to test the efficacy of three pharmaceutical agents that act downstream of the mediobasal hypothalamus to reduce food intake and body weight. These agents include MTII, the glucagon-like peptide (GLP)-1 agonist exenatide and the psychomotor stimulant methylphenidate [ 139 , 140 ]. Both sham-lesioned and CMHL rats exhibited significant reductions in both food intake (lesion −20.8%, control −13.7%) and body weight when treated with exenatide relative to saline-controls [ 139 ].…”

Section: Pharmacological Interventionsmentioning

confidence: 99%

“…These agents include MTII, the glucagon-like peptide (GLP)-1 agonist exenatide and the psychomotor stimulant methylphenidate [ 139 , 140 ]. Both sham-lesioned and CMHL rats exhibited significant reductions in both food intake (lesion −20.8%, control −13.7%) and body weight when treated with exenatide relative to saline-controls [ 139 ]. Using a crossover design study, treatment with methylphenidate in both sham and CHML rats caused a significant decrease in food intake (CMHL −23%, p = 0.008; control −20%, p = 0.002) and body weight compared to saline-treated controls [ 140 ].…”

Section: Pharmacological Interventionsmentioning

confidence: 99%

Hypothalamic Obesity in Craniopharyngioma Patients: Disturbed Energy Homeostasis Related to Extent of Hypothalamic Damage and Its Implication for Obesity Intervention

Roth

2015

JCM

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Hypothalamic obesity (HO) occurs in patients with tumors and lesions in the medial hypothalamic region. Hypothalamic dysfunction can lead to hyperinsulinemia and leptin resistance. This review is focused on HO caused by craniopharyngiomas (CP), which are the most common childhood brain tumors of nonglial origin. Despite excellent overall survival rates, CP patients have substantially reduced quality of life because of significant long-term sequelae, notably severe obesity in about 50% of patients, leading to a high rate of cardiovascular mortality. Recent studies reported that both hyperphagia and decreased energy expenditure can contribute to severe obesity in HO patients. Recognized risk factors for severe obesity include large hypothalamic tumors or lesions affecting several medial and posterior hypothalamic nuclei that impact satiety signaling pathways. Structural damage in these nuclei often lead to hyperphagia, rapid weight gain, central insulin and leptin resistance, decreased sympathetic activity, low energy expenditure, and increased energy storage in adipose tissue. To date, most efforts to treat HO have shown disappointing long-term success rates. However, treatments based on the distinct pathophysiology of disturbed energy homeostasis related to CP may offer options for successful interventions in the future.

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“…The HO rats were treated with GLP1RA. Interestingly, a stronger reduction in food intake was found in rats who received exendin-4 compared to those who received saline injections in both lesioned rats and controls (difference between saline- and exendin-4-injected rats: lesion –20.8%, p = 0.001, control –13.6%, when adjusted for the effect of saline injection) [57], supporting this theory.…”

Section: Treatmentmentioning

confidence: 87%

Hypothalamic Obesity: Prologue and Promise

Abuzzahab

Roth

2019

Horm Res Paediatr

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Hypothalamic obesity (HO) frequently occurs following damage to the medial hypothalamic region, encompassing the arcuate nucleus, the paraventricular nucleus, the ventromedial nucleus, the dorsomedial nucleus, and the dorsal hypothalamic area, which are critically involved in the regulation of satiety and energy balance through neural and humoral connections. HO is most commonly described in the context of craniopharyngioma and its treatment, but it can also occur following other suprasellar tumors, radiation, trauma, or a surgical insult to the hypothalamus. A constellation of loss of satiety and a reduction of the metabolic rate, thermogenesis, and physical activity as well as increased vagal tone and hyperinsulinism with insulin and leptin resistance results in rapid weight gain due to a decreased energy expenditure and increased energy storage in adipose cells. To date, no viable long-term solution for HO has been found, due either to the requirement of intact hypothalamic pathways or to significant side effects. Newer therapeutic modalities focused on the unique pathophysiology of this condition offer potential for successful treatment. In this review, we describe the etiology of HO as well as past/current treatment approaches in the categories of hyperinsulinism, surgical approaches, and targeting energy expenditure/anorectic drugs. We conclude by providing an overview of the clinical trials currently underway.

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Glucagon-Like Peptide-1 Agonist Exendin-4 Leads to Reduction of Weight and Caloric Intake in a Rat Model of Hypothalamic Obesity

Cited by 13 publications

References 84 publications

Glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1: Incretin actions beyond the pancreas

Glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1: Incretin actions beyond the pancreas

Hypothalamic Obesity in Craniopharyngioma Patients: Disturbed Energy Homeostasis Related to Extent of Hypothalamic Damage and Its Implication for Obesity Intervention

Hypothalamic Obesity: Prologue and Promise

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