Glucagon-like peptide 1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as antiobesity strategies. Surprisingly, whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the central nervous system. Serotonin depletion impaired the ability of exendin-4, a clinically used GLP-1 analog, to reduce body weight in rats, suggesting that serotonin is a critical mediator of the energy balance impact of GLP-1 receptor (GLP-1R) activation. Serotonin turnover and expression of 5-hydroxytryptamine (5-HT) 2A (5-HT) and 5-HT serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that the 5-HT, but surprisingly not the 5-HT, receptor is critical for weight loss, anorexia, and fat mass reduction induced by central GLP-1R activation. Importantly, central 5-HT receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin-producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase the electrical activity of the DR serotonin neurons. Finally, our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as a new critical neural substrate for GLP-1 impact on energy homeostasis and expands the current map of brain areas impacted by GLP-1R activation.

Context: There is currently no consensus regarding optimal dose or dose-range of buprenorphine (BUP) for treatment of opioid use disorder (OUD). Objective: To elucidate the relationship between BUP dose and opioid receptor blockade, retention in treatment and illicit opioid drug use. Methods: Systematic review of the scientific literature through searches in the databases MEDLINE and PubMed. Results: The review of the opioid receptor blockade studies did not find evidence that a daily sublingual (SL) BUP tablet dose higher than 16 mg confers added blockade benefit, while doses under 8 mg are insufficient to produce opioid receptor blockade. The data are inconclusive regarding the relative effectiveness of an 8 mg SL BUP tablet dose versus a 16 mg SL BUP tablet dose in terms of opioid receptor blockade. The review did not establish any clear relationship between BUP dose and treatment retention or illicit opioid use. Conclusions: The BUP dose in treatment of OUD should be individualized based on a continuous clinical benefit-risk assessment. Further research is needed to better understand the relationship between dose and efficacy over time in patients with this complex disorder.

Obesity represents one of the most important health problems. Proper adipose tissue expandability is crucial for avoiding metabolic disorders. Furthermore, not all fat depots are functionally equal. Our previous work indicates that the expansion of the mesenteric adipose tissue (MWAT) plays a role in the intestinal barrier. Whether pancreas-associated adipose tissue (PAT) has a specific function is currently unknown. We hypothesize that storage of excess nutrients in PAT and PAT-derived adipokines (such as adiponectin) protect the pancreas against metabolic dysfunction during weight gain/obesity. An initial morphological study showed that PAT has an increased number of small, but fewer large adipocytes relative the adjacent MWAT. We compared the response to a 16-week high-fat diet (HFD)/obesity between PAT, other fat depots and pancreas. We found higher mRNA expression of inflammation markers in MWAT, inguinal (IWAT) and gonadal fat (GWAT), but not in PAT in response to HFD/obesity. HFD also downregulated the expression of insulin receptor and adiponectin in all fat depots, but not in PAT. The pancreas showed an increase in inflammatory and insulin resistance markers only after long-term (16 weeks) HFD exposure, a time point when also PAT displayed a reduction in insulin receptor and adiponectin expression. Smaller adipocytes are typically more functional than large adipocytes. Thus, these data suggest that PAT have an increased capacity for energy storage. This in turn may protect the pancreas against ectopic lipid accumulation and lipotoxicity. Moreover, our data show that PAT is protected against the deleterious effects of HFD, maintaining normal mRNA levels of adiponectin, insulin receptor and markers of inflammation. In summary, we believe that PAT protects the pancreatic beta-cells from lipotoxicity through its increased capacity for energy storage, sustained insulin sensitivity and possibly also increased insulin exposure because of its anatomical location. Disclosure B. Chanclon Garcia: None. Y. Wu: None. E. Banke Nordbeck: None. S. Musovic: None. C.S. Olofsson: None. P. Rorsman: None. I. Wernstedt Asterholm: None.

The white adipocyte hormone adiponectin is released in different molecular forms and a reduction of high-molecular weight (HMW) adiponectin has specifically been associated with the development of metabolic disease. We have recently shown that adiponectin is released via cAMP/epinephrine-stimulated exocytosis, involving activation of beta 3 adrenergic receptors (beta3ARs). However, a number of studies have, seemingly incompatible with the catecholamine-triggered release, reported that insulin (lowers cAMP) increases adiponectin secretion. Here we have pinpointed the differences between insulin- and catecholamine-stimulated short-term adiponectin secretion. Using a combination of biophysical and biochemical techniques applied to mouse and human adipocytes as well as whole animal studies, we show that catecholamines specifically stimulate the rapid exocytosis of high-molecular weight (HMW) adiponectin. In contrast, insulin induces secretion of smaller adiponectin forms only, with slower time kinetics. The catecholamine-stimulated secretion of HMW adiponectin is blunted in adipocytes isolated from obese and diabetic mice (8 weeks high-fat diet) and this secretory defect is paralleled by a ∼50% reduction of serum HMW adiponectin. The insulin-induced release of smaller adiponectin forms is also abrogated i adipocytes from obese/diabetic mice. However, the total serum adiponectin level remains unaltered, likely due to enhanced basal (unstimulated) release of smaller adiponectin forms. Our findings suggest that insulin and catecholamines have entirely different roles in the regulation of adiponectin secretion and demonstrate a previously unknown role of beta3ARs for human white adipocyte physiology. We propose that the reduced levels of HMW adiponectin observed in diabetic individuals, and that have been linked to the development of metabolic disease, is a result of a secretory disturbance largely depending on disrupted adrenergic signaling. Disclosure S. Musovic: None. A.M. Komai: None. E. Banke Nordbeck: None. U.A. Noor: None. I. Wernstedt Asterholm: None. C.S. Olofsson: None. Funding Swedish Diabetes Foundation; Knut and Alice Wallenberg Foundation; Swedish Medical Research Council

Peripancreatic adipose tissue (PAT) is an understudied visceral fat depot that surrounds pancreas and is in touch with spleen and liver. Recent previous studies suggest that obesity-associated PAT inflammation accelerates pancreatic neoplasia in KrasG12D mice and that PAT conditioned-medium from pre-diabetic rats (9 weeks on high-fat diet; HFD) stimulates insulin secretion, proliferation and apoptosis in INS-1 cells. In this study, we aimed to better characterize PAT functionality in the context of HFD-induced obesity. PAT is a very small depot (0,5 ±0,04 mg) with a relatively high number of small adipocytes in unchallenged mice on chow, and we found that PAT expansion is less pronounced at early stages of HFD-feeding compared to the expansion of inguinal (IWAT), gonadal (GWAT) and mesenteric adipose tissues (MWAT). After 8-weeks HFD feeding the expansion of PAT was however comparable to the other three fat depots, but still PAT was more protected against the deleterious effects of HFD on adipose tissue inflammation and insulin resistance as judged by gene expression analysis (adiponectin, insulin receptor and inflammation markers). Feeding after 16-weeks HFD reduced the glucose and lipid uptake in all fat depots however, it was less pronounced in PAT; both fatty acid and glucose oxidation rates were higher in PAT compared to IWAT, GWAT and MWAT. Moreover, we noted that PAT is the only fat depot where the tissue weight correlates positively with liver weight in HFD-induced obese mice, and surgical removal of PAT followed by 16-week-HFD-feeding was associated with increased hepatic triglyceride content and accumulation of more and larger lipid droplets. PAT did not regenerate during this 16-week HFD time course suggesting that its precursor cells reside within the depot. Taken all data together, we propose that PAT, although it is located in the visceral compartment, can be considered as a metabolically/immunologically healthy fat depot that protects against hepatic steatosis in advanced obesity. Disclosure B. Chanclón: None. P. Micallef: None. E. Banke Nordbeck: None. Y. Wu: None. B. Wilder: None. J. Kanerva: None. P. Rorsman: None. I. Wernstedt Asterholm: None.