Glucose control and weight loss are cornerstones of type 2 diabetes treatment. Currently, only glucagon-like peptide-1 (GLP1) analogs are able to achieve both weight loss and glucose tolerance. Both glucose and body weight are regulated by the brain, which contains GLP1 receptors (GLP1R). Even though the brain is poised to mediate the effects of GLP1 analogs, it remains unclear whether the glucose-and body weight-lowering effects of long-acting GLP1R agonists are via direct action on CNS GLP1R or the result of downstream activation of afferent neuronal GLP1R. We generated mice with either neuronal or visceral nerve-specific deletion of Glp1r and then administered liraglutide, a long-acting GLP1R agonist. We found that neither reduction of GLP1R in the CNS nor in the visceral nerves resulted in alterations in body weight or food intake in animals fed normal chow or a high-fat diet. Liraglutide treatment provided beneficial glucose-lowering effects in both chow-and high-fat-fed mice lacking GLP1R in the CNS or visceral nerves; however, liraglutide was ineffective at altering food intake, body weight, or causing a conditioned taste aversion in mice lacking neuronal GLP1R. These data indicate that neuronal GLP1Rs mediate body weight and anorectic effects of liraglutide, but are not required for glucose-lowering effects.
Summary Glucagon-like peptide 1 (GLP-1) is necessary for normal gluco-regulation, and it has been widely presumed that this function reflects the actions of GLP-1 released from enteroendocrine L-cells. To test the relative importance of intestinal vs. pancreatic sources of GLP-1 for physiological regulation of glucose, we administered a GLP-1R antagonist, exendin 9–39 (Ex9), to mice with tissue-specific reactivation of the preproglucagon gene (Gcg). Ex9 impaired glucose tolerance in wild-type mice but had no impact on Gcg null or GLP-1R KO mice suggesting that Ex9 is a true and specific GLP-1R antagonist. Unexpectedly, Ex-9 had no effect on blood glucose in mice with restoration of intestinal Gcg. In contrast, pancreatic reactivation of Gcg fully restored the effect of Ex9 to impair both oral and IP glucose tolerance. These findings suggest an alternative model whereby islet GLP-1 also plays an important role in regulating glucose homeostasis.
The monounsaturated fatty acid palmitoleate (palmitoleic acid) is one of the most abundant fatty acids in serum and tissues, particularly adipose tissue and liver. Its endogenous production by stearoyl-CoA desaturase 1 gives rise to its cis isoform, cis-palmitoleate. Although trans-palmitoleate is also synthesized in humans, it is mainly found as an exogenous source in ruminant fat and dairy products. Recently, palmitoleate was considered to be a lipokine based on evidence demonstrating its release from adipose tissue and its metabolic effects on distant organs. After this finding, research has been performed to determine whether palmitoleate has beneficial effects on metabolism and to elucidate the underlying mechanisms. Thus, the aim of this work was to review the current status of knowledge about palmitoleate, its metabolism, and its influence on metabolic abnormalities. Results have shown mixed cardiovascular effects, direct or inverse correlations with obesity, and hepatosteatosis, but a significant amelioration or prevention of insulin resistance and diabetes. Finally, the induction of palmitoleate release from adipose tissue, dietary intake, and its supplementation are all interventions with a potential impact on certain metabolic diseases. Adv Nutr 2017;8(Suppl):173S-81S.
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