Proglucagon Gene Products
Post-translational processing of preproglucagon results in the production of several peptides in the gut, pancreas, and brain (Fig. 2). These include oxyntomodulin (OXM) and GLP-1 and GLP-2 peptides, which are involved in the regulation of food intake. Prohormone convertase enzymes 1 and 2 cleave preproglucagon and produce different products, depending on the tissue. In the pancreas, glicentin-related pancreatic polypeptide (GRPP), glucagon, and GLP-1 and GLP-2 are produced. The latter two are cosecreted as a large inactive peptide. However, in the intestine and the brain, where the post-translational processing is similar, glicentin, glucagon, GLP-1, and GLP2 are produced. Glucagon remains in the large inactive peptide, whereas glicentin is cleaved to GRPP, with an inactive N-terminal, and oxyntomodulin (Fig. 2) (17).
Oxyntomodulin is a 37-amino-acid peptide produced in the L-cells of the small intestine along with GLP-1 and GLP-2 (71) (Fig. 2).
OXM shows a diurnal variation, with the lowest levels being early in the morning and higher levels peaking in the evening (72). Similar to the rest of the anorexigenic peptides, it is released in proportion to food ingestion and calorie intake (71). Raised plasma levels of OXM have been shown to inhibit gastric acid secretion and motility in both humans and rodents. It also stimulates intestinal glucose uptake and decreases pancreatic enzyme secretion in rats.
Recent evidence supports an anorexigenic role for OXM in both animals and humans. In animals, central administration of OXM has been shown to acutely inhibit food intake (73,74), and chronic intracerebroventricular (ICV) and IP administration reduces both food intake and weight gain (74,75). The latter is thought to be the effect of reduced food intake as well as increased energy expenditure (75). In humans, Cohen and coworkers (76) demonstrated a significant reduction in hunger scores and calorie intake (in a free-choice buffet meal by 19.3%) following parentral administration of OXM. More recently, Wynne et al. (77) have confirmed that the appetite inhibitory effect of OXM is long-lasting, resulting in significant weight reduction. In this study, subcutaneous injections of OXM three times per day for 30 d, in a double-blind placebo-controlled trial in 26 overweight human volunteers, was shown to significantly reduce weight (5.5 lb in the active group compared with 1 lb in those on placebo) (77). Exercise and diet were fixed in both groups. Weight reduction in those subjects was shown to be associated with decreased leptin and increased adiponectin levels (77).
It has been shown that OXM exerts its actions via the GLP-1 and glucagon receptors (78). Therefore, exendin 9-39, which can act either as a GLP-2 receptor antagonist and/ or a GLP-1 agonist, can block the actions of both GLP-1 and OXM (17). GLP-1R is present in the NTS and the arcuate nucleus in addition to its widespread presence peripherally. It is present in the gastrointestinal tract, lung, pancreas, and heart. Interestingly, exendin 9-39 administration into the arcuate nucleus abolishes the peripheral effects of OXM but not that of GLP-1 (74). This suggests an arcuate site of action for OXM, whereas GLP-1 acts via the brain stem. Further evidence suggests different neuronal activation between OXM and GLP-1. OXM has a lower affinity (2-fold) to GLP-1 receptors compared with GLP-1 (79). This may suggest that other mechanisms might be involved in mediating the anorexigenic effects of OXM. Activation of the neuronal c-fos expression in the arcuate nucleus, but not in the brainstem region, was observed following IP administration of OXM and exendin 9-39 (75,78). This pattern of activation is different from that seen following GLP-1 administration (74).
An additional mechanism whereby OXM may exert its effect on appetite is via suppression of ghrelin. In rodents and humans, peripheral administration of OXM results in reduction of circulating ghrelin by 20% (74) and 44% (76), respectively.
The human studies on OXM effect on appetite control may indicate a novel potential role that OXM may have as an antiobesity therapeutic agent. However, more studies research is required to develop the drug into a more user-friendly format (77).
Along with OXM, GLP-1 is also produced by post-translational processing of preproglucagon in the L-cells in the distal ileum (80). Postprandially, GLP-1 is rapidly secreted in response to food intake (81,82). Two equally potent forms (GLP-17-37 and GLP-17-36) have been identified, which undergo rapid inactivation and cleavage by dipeptidyl peptidase IV (DPP IV). As a consequence GLP-1's half-life becomes very short (1-2 min) in the circulation.
Similar to OXM, GLP-1 secretion is regulated by both nutritional and neural/hormonal signals, and its action is mediated via GLP-1R. Actions of GLP-1 on the CNS are complex and are mediated via the dorsal vagal complex acting through the area postrema (83). In rats, similar to OXM, GLP-1 results in c-fos, a marker of neuronal activation, expression in the brainstem (74).
GLP-1 Actions. In addition to its central actions, including the transduction of aver-sive signals, regulation of learning and memory, and neuroprotection, GLP-1 acts as a regulatory peptide in appetite control. GLP-1 inhibits food intake (84,85), reduces gastric secretion and motility, and increases gastric satiety. Central administration of GLP-1 in rodents has been shown to inhibit food intake, which, if continued, results in weight loss (84). Seemingly peripheral administration causes reduced food intake (85-87).
Human studies have shown that peripheral administration of GLP-1 inhibits food intake in normal (88), diabetic (89), and nondiabetic obese men (90) in a dose-dependent manner. Subcutaneous injection of GLP-1 in obese subjects over 5 d was shown to cause a 15% reduction in calorie intake (90) and 0.5 kg weight loss. Although low levels have been shown in obese subjects that normalize after weight loss (86), the anorectic effects of GLP-1 have been shown to be preserved in obesity (90). GLP-1 also decreases gastric emptying, resulting in increased satiety, which may further explain its effect on food intake (91).
GLP-1 is an incretin mimetic that has been found to upregulate insulin gene expression (92). It promotes meal-induced insulin secretion, resulting in reduced blood glucose level. Lower blood glucose level is also achieved via a GLP-1 inhibitory effect on glucagon secretion and reduced gastric emptying. The latter slows the rate of nutrient transit to the small intestine, leading to decreased glycemic excursion after meal ingestion (91,93). Both intravenous and subcutaneous infusions have been shown to normalize blood glucose levels in poorly controlled diabetics. HbA1c was shown to be reduced by 1.3% over a 6-wk period of subcutaneous infusion of GLP-1 in addition to a 2-kg weight loss (94). GLP-1 also stimulates B-cell proliferation and promotes islet cell neogenesis (95). This is thought to be mediated through GLP-1R.
The collective actions of GLP-1 resulting in inhibition of food intake, reduction in weight, a glucose-dependent reduction in blood glucose level, and improvement in diabetes control made it an ideal candidate in the treatment of diabetes. Its therapeutic application is of immense importance in diabetic patients who are increasingly overweight and suffer from drug-related hypoglycaemia.
Trying To Lose Weight Can Be Tough. But... Not Losing Weight and Gaining What You Lost Back, Sucks. If you've ever felt that no matter what you do to lose weight nothing seems to work. If you've ever felt that there has got to be some kind of a system or way to lose weight...but just have not found it yet.