Vance L. Albaugh

Hormonal and Metabolic Effects of Olanzapine and Clozapine Related to Body Weight in Rodents

Objective: To characterize a model of atypical antipsychotic drug‐induced obesity and evaluate its mechanism.

Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery

Roux-en-Y gastric bypass (RYGB) is highly effective in reversing obesity and associated diabetes. Recent observations in humans suggest a contributing role of increased circulating bile acids in mediating such effects. Here we use a diet-induced obesity (DIO) mouse model and compare metabolic remission when bile flow is diverted through a gallbladder anastomosis to jejunum, ileum or duodenum (sham control). We find that only bile diversion to the ileum results in physiologic changes similar to RYGB, including sustained improvements in weight, glucose tolerance and hepatic steatosis despite differential effects on hepatic gene expression. Circulating free fatty acids and triglycerides decrease while bile acids increase, particularly conjugated tauro-β-muricholic acid, an FXR antagonist. Activity of the hepatic FXR/FGF15 signalling axis is reduced and associated with altered gut microbiota. Thus bile diversion, independent of surgical rearrangement of the gastrointestinal tract, imparts significant weight loss accompanied by improved glucose and lipid homeostasis that are hallmarks of RYGB.

Olanzapine promotes fat accumulation in male rats by decreasing physical activity, repartitioning energy and increasing adipose tissue lipogenesis while impairing lipolysis

Olanzapine and other atypical antipsychotics cause metabolic side effects leading to obesity and diabetes; although these continue to be an important public health concern, their underlying mechanisms remain elusive. Therefore, an animal model of these side effects was developed in male Sprague–Dawley rats. Chronic administration of olanzapine elevated fasting glucose, impaired glucose and insulin tolerance, increased fat mass but, in contrast to female rats, did not increase body weight or food intake. Acute studies were conducted to delineate the mechanisms responsible for these effects. Olanzapine markedly decreased physical activity without a compensatory decline in food intake. It also acutely elevated fasting glucose and worsened oral glucose and insulin tolerance, suggesting that these effects are adiposity independent. Hyperinsulinemic-euglycemic clamp studies measuring 14C-2-deoxyglucose uptake revealed tissue-specific insulin resistance. Insulin sensitivity was impaired in skeletal muscle, but either unchanged or increased in adipose tissue depots. Consistent with the olanzapine-induced hyperglycemia, there was a tendency for increased 14C-2-deoxyglucose uptake into fat depots of fed rats and, surprisingly, free fatty acid (FFA) uptake into fat depots was elevated approximately twofold. The increased glucose and FFA uptake into adipose tissue was coupled with increased adipose tissue lipogenesis. Finally, olanzapine lowered fasting plasma FFA, and as it had no effect on isoproterenol-stimulated rises in plasma glucose, it blunted isoproterenol-stimulated in vivo lipolysis in fed rats. Collectively, these results suggest that olanzapine exerts several metabolic effects that together favor increased accumulation of fuel into adipose tissue, thereby increasing adiposity.

A double blind, placebo-controlled, randomized crossover study of the acute metabolic effects of olanzapine in healthy volunteers.

Background and Rationale Atypical antipsychotics exhibit metabolic side effects including diabetes mellitus and obesity. The adverse events are preceded by acute worsening of oral glucose tolerance (oGTT) along with reduced plasma free fatty acids (FFA) and leptin in animal models. It is unclear whether the same acute effects occur in humans. Methodology/Principal Findings A double blind, randomized, placebo-controlled crossover trial was conducted to examine the potential metabolic effects of olanzapine in healthy volunteers. Participants included male (8) and female (7) subjects [18–30 years old, BMI 18.5–25]. Subjects received placebo or olanzapine (10 mg/day) for three days prior to oGTT testing. Primary endpoints included measurement of plasma leptin, oral glucose tolerance, and plasma free fatty acids (FFA). Secondary metabolic endpoints included: triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol, heart rate, blood pressure, body weight and BMI. Olanzapine increased glucose Area Under the Curve (AUC) by 42% (2808±474 vs. 3984±444 mg/dl·min; P = 0.0105) during an oGTT. Fasting plasma leptin and triglycerides were elevated 24% (Leptin: 6.8±1.3 vs. 8.4±1.7 ng/ml; P = 0.0203) and 22% (Triglycerides: 88.9±10.1 vs. 108.2±11.6 mg/dl; P = 0.0170), whereas FFA and HDL declined by 32% (FFA: 0.38±0.06 vs. 0.26±0.04 mM; P = 0.0166) and 11% (54.2±4.7 vs. 48.9±4.3 mg/dl; P = 0.0184), respectively after olanzapine. Other measures were unchanged. Conclusions/Significance Olanzapine exerts some but not all of the early endocrine/metabolic changes observed in rodent models of the metabolic side effects, and this suggest that antipsychotic effects are not limited to perturbations in glucose metabolism alone. Future prospective clinical studies should focus on identifying which reliable metabolic alterations might be useful as potential screening tools in assessing patient susceptibility to weight gain and diabetes caused by atypical antipsychotics. Trial Registration ClinicalTrials.gov NCT00741026

Ileal interposition improves glucose tolerance and insulin sensitivity in the obese Zucker rat

The hindgut hypothesis posits improvements in Type 2 diabetes after gastric bypass surgery are due to enhanced delivery of undigested nutrients to the ileum, which increase incretin production and insulin sensitivity. The present study investigates the effect of ileal interposition (IT), surgically relocating a segment of distal ileum to the proximal jejunum, on glucose tolerance, insulin sensitivity, and glucose transport in the obese Zucker rat. Two groups of obese Zucker rats were studied: IT and sham surgery ad libitum fed (controls). Changes in food intake, body weight and composition, glucose tolerance, insulin sensitivity and tissue glucose uptake, and insulin signaling as well as plasma concentrations of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide were measured. The IT procedure did not significantly alter food intake, body weight, or composition. Obese Zucker rats demonstrated improved glucose tolerance 3 wk after IT compared with the control group (P < 0.05). Euglycemic, hyperinsulinemic clamp and 1-[(14)C]-2-deoxyglucose tracer studies indicate that IT improves whole body glucose disposal, insulin-stimulated glucose uptake, and the ratio of phospho- to total Akt (P < 0.01 vs. control) in striated muscle. After oral glucose, the plasma concentration of glucagon-like peptide-1 was increased, whereas GIP was decreased following IT. Enhanced nutrient delivery to the ileum after IT improves glucose tolerance, insulin sensitivity and muscle glucose uptake without altering food intake, body weight, or composition. These findings support the concept that anatomic and endocrine alterations in gut function play a role in the improvements in glucose homeostasis after the IT procedure.

Early Increases in Bile Acids Post Roux-en-Y Gastric Bypass Are Driven by Insulin-Sensitizing, Secondary Bile Acids

CONTEXT Roux-en-Y gastric bypass (RYGB) is the most effective treatment for morbid obesity and resolution of diabetes. Over the last decade, it has become well accepted that this resolution of diabetes occurs before significant weight loss; however, the mechanisms behind this effect remain unknown and could represent novel therapeutic targets for obesity and diabetes. Bile acids have been identified as putative mediators of these weight loss-independent effects. OBJECTIVE To identify the longitudinal changes in bile acids after RYGB, which may provide mechanistic insight into the weight loss-independent effects of RYGB. DESIGN Observational study before/after intervention. SETTING Academic medical center. PATIENTS/PARTICIPANTS Samples were collected from morbidly obese patients (n = 21) before and after RYGB. INTERVENTION RYGB. MAIN OUTCOME MEASURES Seventeen individual bile acid species were measured preoperatively and at 1, 6, 12, and 24 months postoperatively. Anthropometric, hormonal, and hyperinsulinemic-euglycemic clamp data were also examined to identify physiological parameters associated with bile acid changes. RESULTS Fasting total plasma bile acids increased after RYGB; however, increases were bimodal and were observed only at 1 (P < .05) and 24 months (P < .01). One-month increases were secondary to surges in ursodeoxycholic acid and its glycine and taurine conjugates, bacterially derived bile acids with putative insulin-sensitizing effects. Increases at 24 months were due to gradual rises in primary unconjugated bile acids as well as deoxycholic acid and its glycine conjugate. Plasma bile acid changes were not significantly associated with any anthropometric or hormonal measures, although hepatic insulin sensitivity was significantly improved at 1 month. CONCLUSIONS Overall findings suggest that bacterially derived bile acids may mediate the early improvements at 1 month after RYGB. Future studies should examine the changes in specific bile acid chemical species after bariatric procedures and bile acid-specific signaling changes.

Atypical Antipsychotics Rapidly and Inappropriately Switch Peripheral Fuel Utilization to Lipids, Impairing Metabolic Flexibility in Rodents

Patients taking atypical antipsychotics are frequented by serious metabolic (eg, hyperglycemia, obesity, and diabetes) and cardiac effects. Surprisingly, chronic treatment also appears to lower free fatty acids (FFAs). This finding is paradoxical because insulin resistance is typically associated with elevated not lower FFAs. How atypical antipsychotics bring about these converse changes in plasma glucose and FFAs is unknown. Chronic treatment with olanzapine, a prototypical, side effect prone atypical antipsychotic, lowered FFA in Sprague-Dawley rats. Olanzapine also lowered plasma FFA acutely, concomitantly impairing in vivo lipolysis and robustly elevating whole-body lipid oxidation. Increased lipid oxidation was evident from accelerated losses of triglycerides after food deprivation or lipid challenge, elevated FFA uptake into most peripheral tissues (∼2-fold) except heart, rises in long-chain 3-hydroxylated acyl-carnitines observed in diabetes, and rapid suppression of the respiratory exchange ratio (RER) during the dark cycle. Normal rises in RER following refeeding, a sign of metabolic flexibility, were severely blunted by olanzapine. Increased lipid oxidation in muscle could be explained by ∼50% lower concentrations of the negative cytoplasmic regulator of carnitine palmitoyltransferase I, malonyl-CoA. This was associated with loss of anapleurotic metabolites and citric acid cycle precursors of malonyl-CoA synthesis rather than adenosine monophosphate-activated kinase activation or direct ACC1/2 inhibition. The ability of antipsychotics to lower dark cycle RER in mice corresponded to their propensities to cause metabolic side effects. Our studies indicate that lipocentric mechanisms or altered intermediary metabolism could underlie the FFA lowering and hyperglycemia (Randle cycle) as well as some of the other side effects of atypical antipsychotics, thereby suggesting strategies for alleviating them.

Bile acids and bariatric surgery

Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), are the most effective and durable treatments for morbid obesity and potentially a viable treatment for type 2 diabetes (T2D). The resolution rate of T2D following these procedures is between 40 and 80% and far surpasses that achieved by medical management alone. The molecular basis for this improvement is not entirely understood, but has been attributed in part to the altered enterohepatic circulation of bile acids. In this review we highlight how bile acids potentially contribute to improved lipid and glucose homeostasis, insulin sensitivity and energy expenditure after these procedures. The impact of altered bile acid levels in enterohepatic circulation is also associated with changes in gut microflora, which may further contribute to some of these beneficial effects. We highlight the beneficial effects of experimental surgical procedures in rodents that alter bile secretory flow without gastric restriction or altering nutrient flow. This information suggests a role for bile acids beyond dietary fat emulsification in altering whole body glucose and lipid metabolism strongly, and also suggests emerging roles for the activation of the bile acid receptors farnesoid x receptor (FXR) and G-protein coupled bile acid receptor (TGR5) in these improvements. The limitations of rodent studies and the current state of our understanding is reviewed and the potential effects of bile acids mediating the short- and long-term metabolic improvements after bariatric surgery is critically examined.

Recent advances in metabolic and bariatric surgery

Obesity and its associated medical conditions continue to increase and add significant burden to patients, as well as health-care systems, worldwide. Bariatric surgery is the most effective treatment for severe obesity and its comorbidities, and resolution of diabetes is weight loss-independent in the case of some operations. Although these weight-independent effects are frequently described clinically, the mechanisms behind them are not well understood and remain an intense area of focus in the growing field of metabolic and bariatric surgery. Perceptions of the mechanisms responsible for the beneficial metabolic effects of metabolic/bariatric operations have shifted from being mostly restrictive and malabsorption over the last 10 to 15 years to being more neuro-hormonal in origin. In this review, we describe recent basic and clinical findings of the major clinical procedures (adjustable gastric banding, vertical sleeve gastrectomy, Roux-en-Y gastric bypass, and biliopancreatic diversion) as well as other experimental procedures (ileal interposition and bile diversion) that recapitulate many of the metabolic effects of these complex operations in a simpler fashion. As the role of bile acids and the gut microbiome on metabolism is becoming increasingly well described, their potential roles in these improvements following metabolic surgery are becoming better appreciated. Bile acid and gut microbiome changes, in light of recent developments, are discussed in the context of these surgical procedures, as well as their implications for future study.

Metabolic responses to exogenous ghrelin in obesity and early after Roux-en-Y gastric bypass in humans

Ghrelin is a gastric‐derived hormone that stimulates growth hormone (GH) secretion and has a multi‐faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux‐en‐Y gastric bypass (RYGB).