calcitonin and Obesity

A growing appreciation of the overlapping neuroendocrine mechanisms controlling energy balance has highlighted combination therapies as a promising strategy to enhance sustained weight loss. Here, we investigated whether amylin- and glucagon-like-peptide-1 (GLP-1)-based combination therapies produce greater food intake- and body weight-suppressive effects compared to monotherapies in both lean and diet-induced obese (DIO) rats. In chow-maintained rats, systemic amylin and GLP-1 combine to reduce meal size. Furthermore, the amylin and GLP-1 analogs salmon calcitonin (sCT) and liraglutide produce synergistic-like reductions in 24 hours energy intake and body weight. The administration of sCT with liraglutide also led to a significant enhancement in cFos-activation in the dorsal-vagal-complex (DVC) compared to mono-therapy, suggesting an activation of distinct, yet overlapping neural substrates in this critical energy balance hub. In DIO animals, long-term daily administration of this combination therapy, specifically in a stepwise manner, results in reduced energy intake and greater body weight loss over time when compared to chronic mono- and combined-treated groups, without affecting GLP-1 receptor, preproglucagon or amylin-receptor gene expression in the DVC.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Calcitonin; Diet, High-Fat; Eating; Energy Intake; Energy Metabolism; Glucagon-Like Peptide 1; Islet Amyloid Polypeptide; Male; Obesity; Rats; Receptors, Glucagon; Weight Loss

We previously reported that oral delivery of salmon calcitonin (sCT) improved energy and glucose homeostasis and attenuated diabetic progression in animal models of diet-induced obesity (DIO) and type 2 diabetes, although the glucoregulatory mode of action was not fully elucidated. In the present study we hypothesized that oral sCT as pharmacological intervention 1) exerted anti-hyperglycemic efficacy, and 2) enhanced insulin action in DIO-streptozotocin (DIO-STZ) diabetic rats. Diabetic hyperglycemia was induced in male selectively bred DIO rats by a single low dose (30mg/kg) injection of STZ. Oral sCT by gavage was delivered as once-daily administration with lead-in (2mg/kg) and maintenance (0.5mg/kg) dose of oral sCT for a total of 21 days. Food intake, body weight, blood glucose, HbA1c, glucose and insulin tolerance test, and parameters of insulin sensitivity were investigated. Plasma glucoregulatory hormones and pancreatic insulin content were analyzed. Oral sCT treatment induced a pronounced anorectic action during the 7 days lead-in period and markedly reduced food intake and body weight in conjunction with improved glucose homeostasis. During the maintenance period, oral sCT normalized food intake and attenuated weight loss, albeit sustained glycemic control by reducing fasting blood glucose and HbA1c levels compared to those of vehicle-treated rats at the end of study. Notably, plasma levels of insulin, glucagon, leptin and adiponectin were unaltered, albeit insulin action was enhanced in conjunction with protection of pancreatic insulin content. The results of the present study indicate that oral sCT exerts a novel insulin-sensitizing effect to improve glucose metabolism in obesity and type 2 diabetes.

Topics: Administration, Oral; Animals; Blood Glucose; Body Weight; Calcitonin; Diabetes Mellitus, Experimental; Diet; Eating; Glucose Tolerance Test; Homeostasis; Hypoglycemic Agents; Insulin; Male; Obesity; Rats

Oral salmon calcitonin (sCT) has demonstrated clinical efficacy in treating osteoporosis in postmenopausal women. The postmenopausal state is also associated with obesity-related insulin resistance (IR) and type 2 diabetes. The aim of this study was to investigate the preventive effects of oral sCT on energy and glucose homeostasis in high-fat diet (HFD)- and ovariectomy (OVX)-induced obese rats. Furthermore, the weight-regulatory and gluco-regulatory effects of short-term oral sCT intervention on HFD-induced obese rats were explored.. For prevention, female rats exposed to HFD with or without OVX were treated with oral sCT for 5 weeks. As intervention, HFD-induced obese male rats were treated with oral sCT for 4 days. Body weight, food intake, and plasma glucose, insulin, and leptin levels were measured, and the clinical homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated. In addition, oral glucose tolerance was evaluated in the systemic and portal circulations.. For prevention, oral sCT reduced body weight by ∼16% to 19% (P < 0.001), reduced plasma insulin and leptin by ∼50%, and improved impaired fasting glycemia (P < 0.05) concomitantly with amelioration of IR (HOMA-IR; P < 0.01) in HFD- and OVX-induced obesity. Furthermore, oral sCT significantly reduced the incremental area under the curve for plasma glucose and insulin by ∼40% and ∼70%, respectively, during glucose tolerance testing. As intervention in HFD-induced obese rats, oral sCT reduced body weight, fasting glycemia, and insulinemia in conjunction with HOMA-IR (P < 0.001). Finally, oral sCT alleviated glucose intolerance predominantly in the portal circulation.. Oral sCT treatment displays weight-regulatory and glucoregulatory efficacy in HFD- and OVX-induced obese rats, indicating the clinical usefulness of oral sCT in postmenopausal obesity-related IR and type 2 diabetes.

Topics: Animals; Blood Glucose; Body Weight; Calcitonin; Diabetes Mellitus, Type 2; Diet, High-Fat; Fasting; Female; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Male; Obesity; Ovariectomy; Rats; Rats, Sprague-Dawley

To investigate the effects of acute and chronic administration of a novel oral formulation of salmon calcitonin (sCT) on glycaemic control, glucose homeostasis and body weight regulation in diet-induced obese (DIO) rats-an animal model of obesity-related insulin resistance and type 2 diabetes.. DIO rats were acutely given a single dose of oral sCT (0.5 and 2 mg/kg), its oral vehicle N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC) or injectable sCT (5 and 10 µg/kg) (n = 8), followed by oral glucose tolerance test (OGTT). Other DIO rats were chronic treated twice daily with oral vehicle 5-CNAC (n = 6), oral sCT (0.5 and 2 mg/kg) or injectable sCT (10 µg/kg) (n = 8). Fasting and postprandial glucose and pancreatic hormones, body weight and insulin sensitivity were assessed.. A single dose of oral sCT acutely reduced glucose and insulin area under the curve during OGTT by approximately 65 and 85%, respectively, compared with vehicle (p < 0.001). Chronic treatment with oral sCT significantly reduced both fasting and postprandial glucose and insulin levels by approximately 1.5 mM and 65%, respectively, compared with vehicle. Oral sCT concomitantly improved insulin sensitivity (homeostatic model assessment, HOMA). In contrast, injectable sCT resembling higher systemic exposure did not improve glycaemic control, either acutely or during chronic treatment. Furthermore, both oral and injectable sCT reduced body weight by 15% compared with vehicle (p < 0.05).. A novel oral form of sCT showed antidiabetic effects in DIO rats by improving glycaemic control, glucose homeostasis, insulin sensitivity and body weight.

Topics: Administration, Oral; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Calcitonin; Diabetes Mellitus, Type 2; Homeostasis; Hypoglycemic Agents; Insulin; Insulin Resistance; Obesity; Rats

Chronic administration of anorexigenic substances to experimental animals by injections or continuous infusion typically produces no effect or a transient reduction in daily food intake and body weight. Our aim was to identify an intermittent dosing strategy for intraperitoneal infusion of salmon calcitonin (sCT), a homolog of amylin that produces a sustained 25-35% reduction in daily food intake and adiposity in diet-induced obese rats. Rats (649 +/- 10 g body wt, 27 +/- 1% body fat), with intraperitoneal catheters tethered to infusion swivels, had free access to a 45% fat diet. Food intake, body weight, and adiposity during the 7-wk test period were relatively stable in the vehicle-treated rats (n = 16). None of 10 sCT dosing regimens administered in succession to a second group of rats (n = 18) produced a sustained 25-35% reduction in daily food intake for >5 days, although body weight and adiposity were reduced by 9% (587 +/- 12 vs. 651 +/- 14 g) and 22% (20.6 +/- 1.2 vs. 26.5 +/- 1.1%), respectively, across the 7-wk period. The declining inhibitory effect of sCT on daily food intake with the 6-h interinfusion interval appeared to be due in part to an increase in food intake between infusions. The declining inhibitory effect of sCT on daily food intake with the 2- to 3-h interinfusion interval suggested possible receptor downregulation and tolerance to frequent sCT administration; however, food intake increased dramatically when sCT was discontinued for 1 day after apparent loss of treatment efficacy. Together, these results demonstrate the activation of a potent homeostatic response to increase food intake when sCT reduces food intake and energy reserves in diet-induced obese rats.

Topics: Adiposity; Amyloid; Animals; Body Weight; Calcitonin; Diet; Eating; Infusions, Parenteral; Islet Amyloid Polypeptide; Male; Obesity; Rats; Rats, Sprague-Dawley