The Human Monoacylglycerol Acyltransferase 2 Inhibitor VB-85387 Is Associated With Weight Loss in Mice With Obesity.

The health benefits of caloric restriction, including decreasing body fat and blood glucose, differ between males and females and this difference depends on the age at which caloric restriction begins.

What Can We Learn From Mouse Models About Bile Acid-Mediated Changes After Bariatric Surgery?

Obesity is a contributing factor to insulin resistance and type 2 diabetes. The aim of this study was to study the therapeutic potential of intestinal electrical stimulation (IES) for obesity and associated glucose intolerance and insulin resistance in diet-induced obesity (DIO) rats. DIO rats were divided into two groups to receive sham or IES for 8 weeks. Oral glucose tolerance and insulin tolerance tests were performed. Gastric emptying and small bowel transit tests were performed. Blood samples were collected for the analysis of insulin and free fatty acid (FFA). Chronic IES reduced food intake and body weight and decreased the adiposity index in DIO rats. Compared with chow-fed rats, DIO rats had an elevated fasting plasma glucose level, impaired glucose tolerance, and impaired insulin sensitivity, which were improved after chronic IES. FFA was elevated in DIO rats and suppressed with IES. Chronic IES delayed gastric emptying but accelerated small bowel transit. IES reduces food intake and body weight and improves glucose tolerance and insulin resistance in DIO rats. The ameliorating effect on glycemic control may be due to the weight loss and suppression of plasma FFA. Other mechanisms such as the modulation of gastrointestinal transit may also be involved.

Weight loss reduces abdominal fat and improves insulin action in middle-aged and older men with impaired glucose tolerance

Objective:High-protein diets (HPDs) are associated with greater satiety and weight loss than diets rich in other macronutrients. The exact mechanisms by which HPDs exert their effects are unclear. However, evidence suggests that the sensing of amino acids produced as a result of protein digestion may have a role in appetite regulation and satiety. We investigated the effects of l-phenylalanine (L-Phe) on food intake and glucose homeostasis in rodents.Methods:We investigated the effects of the aromatic amino-acid and calcium-sensing receptor (CaSR) agonist l-phenylalanine (L-Phe) on food intake and the release of the gastrointestinal (GI) hormones peptide YY (PYY), glucagon-like peptide-1 (GLP-1) and ghrelin in rodents, and the role of the CaSR in mediating these effects in vitro and in vivo. We also examined the effect of oral l-Phe administration on glucose tolerance in rats.Results:Oral administration of l-Phe acutely reduced food intake in rats and mice, and chronically reduced food intake and body weight in diet-induced obese mice. Ileal l-Phe also reduced food intake in rats. l-Phe stimulated GLP-1 and PYY release, and reduced plasma ghrelin, and also stimulated insulin release and improved glucose tolerance in rats. Pharmacological blockade of the CaSR attenuated the anorectic effect of intra-ileal l-Phe in rats, and l-Phe-induced GLP-1 release from STC-1 and primary L cells was attenuated by CaSR blockade.Conclusions:l-Phe reduced food intake, stimulated GLP-1 and PYY release, and reduced plasma ghrelin in rodents. Our data provide evidence that the anorectic effects of l-Phe are mediated via the CaSR, and suggest that l-Phe and the CaSR system in the GI tract may have therapeutic utility in the treatment of obesity and diabetes. Further work is required to determine the physiological role of the CaSR in protein sensing in the gut, and the role of this system in humans.

Amylin and GLP-1 agonism induce a well-known anorexic effect at dose initiation, which is managed by dose escalation. In this study we investigated how to optimize tolerability while maintaining efficacy of a novel, highly potent dual amylin and calcitonin receptor agonist (DACRA), KBP-089. Furthermore, we tested the GLP-1 add-on potential of KBP-089 in high-fat diet (HFD)-fed rats. KBP-089 potently activated both the amylin and calcitonin receptors in vitro and demonstrated a prolonged receptor activation as well as a potent reduction of acute food intake. HFD rats dosed every day or every second day obtained equal weight loss at study end, albeit with an uneven reduction in both food intake and body weight in rats dosed every second day. In a 4-fold dose escalation, KBP-089 induced a transient reduction in food intake at every escalation step, with reducing magnitude over time, and the following treatment with 2.5, 10, and 40 µg/kg resulted in an ~15% vehicle-corrected weight loss, a corresponding reduction in adipose tissue (AT), and, in all treatment groups, improved oral glucose tolerance (P < 0.01). Twofold and linear escalations suppressed body weight evenly with no significant reduction in food intake at either escalation step. KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) reduced 24-h food intake by 29% and 37% compared with vehicle, respectively; however, when they were combined, 24-h food intake was reduced by 87%. Chronically, KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) lowered body weight 8% and 2% in HFD rats, respectively, whereas the combination resulted in a 12% body weight reduction. Moreover, the combination improved glucose tolerance (P < 0.05). In conclusion, DACRAs act complementarily with GLP-1 on food intake and body weight. Furthermore, on escalation, KBP-089 was well tolerated and induced and sustained a significant weight loss and a reduction in AT in lean and HFD rats, underscoring the potential of KBP-089 as an anti-obesity agent.

An Albumin-Exendin-4 Conjugate Engages Central and Peripheral Circuits Regulating Murine Energy and Glucose Homeostasis

Background: High-fat and very low-carbohydrate based ketogenic diets have gained considerable popularity as a non-pharmacological strategy for treating obesity due to their potential to enhance weight loss and improve glucose homeostasis. However, the effectiveness of a ketogenic diet towards metabolic health is equivocal. Methods: Male and female mice were fed a 60% cocoa butter fat-based high-fat diet for 16-weeks to induce obesity, following which mice were transitioned to either an 85% cocoa butter fat-based ketogenic diet (KD) , a 10% cocoa butter fat-based low-fat diet (LFD) , or maintained on a high-fat diet for an additional 8-weeks. All experimental diets were matched for sucrose and protein content, and contained an identical micronutrient profile, with complex carbohydrates being the primary carbohydrate source in the LFD. Results: The transition to a KD was ineffective at inducing significant body fat loss, improving glucose homeostasis, or enhancing insulin sensitivity in obese male and female mice. Alternatively, obese male and female mice transitioned to a LFD exhibited a marked decrease in body weight, which was primarily attributed to a loss of adiposity, and an improved glucose tolerance during an intraperitoneal glucose tolerance test. Despite the improvements in glucose tolerance, insulin sensitivity remained impaired in obese male mice transitioned to a LFD, whereas it was improved in obese female mice. These salutary actions attributed to a transition to a LFD resulting in beneficial body composition changes and improved glucose tolerance, may in part be due to the trend to mild reductions and increases in food intake and energy expenditure, respectively. Conclusions: Our findings suggest that careful consideration should be taken when consuming a KD as a non-pharmacological strategy for treating obesity, whereas consumption of a diet low in saturated fat and rich in complex carbohydrates imparts numerous beneficial actions. Disclosure A.A.Greenwell: None. G.Lopaschuk: None. R.A.Batran: None. J.R.Ussher: None. C.T.Saed: None. S.Tabatabaei dakhili: None. K.Ho: None. K.Gopal: None. J.S.F.Chan: None. O.Kaczmar: None. S.A.Dyer: None. F.Eaton: None.

To elucidate the specific role of gastric vs. intestinal manipulations in the regulation of body weight and glucose homeostasis. The effects of intestinal bypass alone (duodenal-jejunal bypass -DJB) and gastric resection alone (SG) in Zucker Diabetic Fatty (ZDF) rats were compared. Additional animals underwent a combination procedure (SG + DJB). Outcome measures included changes in weight, food intake (FI), oral glucose tolerance (GT) and gut hormones. DJB did not substantially affect weight and FI, whereas SG significantly reduced weight gain and food consumption. DJB rats showed weight-independent improvement in GT, which improved less after SG. Furthermore, SG significantly suppressed plasma ghrelin and increased insulin, glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide and peptide YY response to oral glucose whereas DJB had no effects on postprandial levels of these hormones. DJB restored postprandial glucagon suppression in diabetic rats whereas SG did not affect glucagon response. The combination procedure (SG + DJB) induced greater weight loss and better GT than SG alone without reducing food intake further. These findings reveal a dominant role of the stomach in the regulation of body weight and incretin response to oral glucose whereas intestinal bypass primarily affects glucose homeostasis by a weight-, insulin- and incretin-independent mechanism.

Alternate-day fasting (ADF) causes body weight (BW) loss in humans and rodents. However, it is not clear that ADF while maintaining a high-fat (HF) diet results in weight loss and the accompanying improvement in control of circulating glucose. We tested the hypotheses that a high-fat ADF protocol in obese mice would result in (i) BW loss, (ii) improved glucose control, (iii) fluctuating phenotypes on 'fasted' days when compared to 'fed' days and (iv) induction of torpor on 'fasted days'. We evaluated the physiological effects of ADF in diet-induced obese mice for BW, heart rate (HR), body temperature (Tb ), glucose tolerance, insulin responsiveness, blood parameters (leptin, insulin, free fatty acids) and hepatic gene expression. Diet-induced obese male C57BL/6J mice lost one-third of their pre-diet BW while on an ADF diet for 10weeks consisting of HF food. The ADF protocol improved glucose tolerance and insulin sensitivity, although mice on a fast day were less glucose tolerant than the same mice on a fed day. ADF mice on a fast day had low circulating insulin, but had an enhanced response to an insulin-assisted glucose tolerance test, suggesting the impaired glucose tolerance may be a result of insufficient insulin production. On fed days, ADF mice were the warmest, had a high HR and displayed hepatic gene expression and circulating leptin that closely mimicked that of mice fed an ad lib HF diet. ADF mice never entered torpor as assessed by HR and Tb . However, on fast days, they were the coolest, had the slowest HR, and displayed hepatic gene expression and circulating leptin that closely mimicked that of Chow-Fed mice. Collectively, the ADF regimen with a HF diet in obese mice results in weight loss, improved blood glucose control, and daily fluctuations in selected physiological and biochemical parameters in the mouse.

The surgical treatment for obesity promotes massive weight loss and early improvement in co-morbid conditions such as type-2 diabetes. Because surgically mediated glycemic improvements are immediate, the mechanisms involved appear to be weight loss independent. Ileal interposition has been used to gain understanding of the relative role that the lower intestine plays in mediating metabolic improvement. Here, we report that ileal interposition is sufficient for improving glucose tolerance in a low-dose streptozotocin-treated diabetic rat model as well as in normal rats with no effect on body weight. Male Long-Evans rats were treated with streptozotocin (35 mg/kg) or left untreated and then received sham or ileal interposition. Body weight was measured as well as glucose and insulin tolerance. Plasma insulin and gut hormones were measured during the glucose tolerance test. Streptozotocin treatment resulted in hyperglycemia within 48 h after treatment. Diabetic rats with ileal interposition showed improvement in glucose tolerance as early as 4 weeks after surgery compared to sham (p < 0.05). By 11 weeks after surgery glucose and insulin tolerance was markedly improved in interposed-diabetic compared to sham-diabetic rats (p < 0.05). Normal non-diabetic rats showed improved glucose tolerance after ileal interposition compared to sham (p < 0.05). Insulin secretion was increased in interposed rats following glucose administration (p < 0.05). The ileal-derived hormones glucagon like peptide-1 (GLP-1), peptide YY (PYY), and glucagon were all significantly elevated in the ileal interposed rats (p < 0.01). Gastric inhibitory polypeptide (GIP) was unchanged. In neither study did body weight between the surgical groups differ at any time point. Ileal interposition effectively improves glucose tolerance in streptozotocin-diabetic and euglycemic rats. Enhanced insulin secretion can explain the lowered glucose concentrations in euglycemic rats following ileal interposition. Ileal interposition is associated with dramatically elevated ileal hormones, GLP-1, PYY, and glucagon (p < 0.01) with no change in the duodenal hormone GIP.

Enhanced stimulation of the lower gut is hypothesized to play a key role in the weight loss and resolution of diabetes following bariatric surgeries. Ileal transposition (IT) permits study of the effects of direct lower gut stimulation on body weight, glucose homeostasis and other metabolic adaptations without the confounds of gastric restriction or foregut exclusion. However, the underlying mechanisms and the length of the ileum sufficient to produce metabolic benefits following IT surgery remain largely unknown. To determine the effects of transposing varying lengths of the ileum to upper jejunum on food intake, body weight, glucose tolerance and lower gut hormones, and the expression of key markers of glucose and lipid metabolism in skeletal muscle and adipose tissue in rats. Adult male Sprague-Dawley rats (n=9/group) were subjected to IT surgery with translocation of 5, 10 or 20 cm of the ileal segment to proximal jejunum or sham manipulations. Daily food intake and body weight were recorded, and an intraperitoneal glucose tolerance test was performed. Blood samples were assayed for hormones and tissue samples for mRNA (RT-qPCR) and/or protein abundance (immunoblotting) of regulatory metabolic markers. We demonstrate that IT surgery exerts ileal length-dependent effects on multiple parameters including: (1) decreased food intake and weight gain, (2) improved glucose tolerance, (3) increased tissue expression and plasma concentrations of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), and decreased leptin concentrations and (4) upregulation of key markers of glucose metabolism (glucose transporter-4 (GLUT-4), insulin receptor substrate 1 (IRS-1), adenosine monophosphate-activated protein kinase (AMPK), hexokinase (HK) and phosphofructokinase (PFK)) together with a downregulation of lipogenic markers (fatty acid synthase (FAS)) in muscle and adipose tissue. Together, our data demonstrate that the reduction in food intake and weight gain, increase in lower gut hormones, glycemic improvements and associated changes in tissue metabolic markers following IT surgery are dependent on the length of the transposed ileum.

Ghrelin, through action on its receptor, GH secretagogue receptor type 1a (GHS-R1a), exerts a variety of metabolic functions including stimulation of appetite and weight gain and suppression of insulin secretion. In the present study, we examined the effects of novel small-molecule GHS-R1a antagonists on insulin secretion, glucose tolerance, and weight loss. Ghrelin dose-dependently suppressed insulin secretion from dispersed rat islets. This effect was fully blocked by a GHS-R1a antagonist. Consistent with this observation, a single oral dose of a GHS-R1a antagonist improved glucose homeostasis in an ip glucose tolerance test in rat. Improvement in glucose tolerance was attributed to increased insulin secretion. Daily oral administration of a GHS-R1a antagonist to diet-induced obese mice led to reduced food intake and weight loss (up to 15%) due to selective loss of fat mass. Pair-feeding experiments indicated that weight loss was largely a consequence of reduced food intake. The impact of a GHS-R1a antagonist on gastric emptying was also examined. Although the GHS-R1a antagonist modestly delayed gastric emptying at the highest dose tested (10 mg/kg), delayed gastric emptying does not appear to be a requirement for weight loss because lower doses produced weight loss without an effect on gastric emptying. Consistent with the hypothesis that ghrelin regulates feeding centrally, the anorexigenic effects of potent GHS-R1a antagonists in mice appeared to correspond with their brain exposure. These observations demonstrate that GHS-R1a antagonists have the potential to improve the diabetic condition by promoting glucose-dependent insulin secretion and promoting weight loss.

Angiotensin-converting enzyme inhibition reduces food intake and weight gain and improves glucose tolerance in melanocortin-4 receptor deficient female rats

Insufficient sleep is associated with changes in glucose tolerance, insulin secretion, and insulin action. Despite widespread use of weight-loss diets for metabolic risk reduction, the effects of insufficient sleep on glucose regulation in overweight dieters are not known. To examine the consequences of recurrent sleep restriction on 24-hour blood glucose control during diet-induced weight loss, 10 overweight and obese adults (3F/7M; mean [SD] age 41 [5] y; BMI 27.4 [2.0] kg/m2) completed two 14-day treatments with hypocaloric diet and 8.5 or 5.5-h nighttime sleep opportunity in random order 7 [3] months apart. Oral and intravenous glucose tolerance test (IVGTT) data, fasting lipids and free-fatty acids (FFA), and 24-hour blood glucose, insulin, C-peptide, and counter-regulatory hormone measurements were collected after each treatment. Participants had comparable weight loss (1.0 [0.3] BMI units) during each treatment. Bedtime restriction reduced sleep by 131 [30] min/day. Recurrent sleep curtailment decreased 24-hour serum insulin concentrations (i.e. enhanced 24-hour insulin economy) without changes in oral glucose tolerance and 24-hour glucose control. This was accompanied by a decline in fasting blood glucose, increased fasting FFA which suppressed normally following glucose ingestion, and lower total and LDL cholesterol concentrations. Sleep-loss-related changes in counter-regulatory hormone secretion during the IVGTT limited the utility of the test in this study. In conclusion, sleep restriction enhanced 24-hour insulin economy without compromising glucose homeostasis in overweight individuals placed on a balanced hypocaloric diet. The changes in fasting blood glucose, insulin, lipid and FFA concentrations in sleep-restricted dieters resembled the pattern of human metabolic adaptation to reduced carbohydrate availability.