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GLP-1 and Appetite Suppression

There has been an increased use of GLP-1 analogs in patients with diabetes over the past two years as the advent of daily dosing has made medication adherence simpler and more clinicians are comfortable with the available choices.

As patients learn more about these medications they hear information from others about potential benefits and often come to your office with a goal in mind. Over the past 6-8 weeks we have been speaking to members of our Medical Advisory Board about the use of GLP-1 for Appetite Suppression and they directed us to Dr. Daniel Drucker from the Samuel Lunenfeld Research Institute at Mount Sinai Hospital in Toronto. Dr. Drucker maintains www.Glucagon.com, a website dedicated to the study of glucagon-like peptides. He has shared his information with us and we have prepared a synopsis for you.

The information in a publication in 1996 in the journal Nature1 that ICV GLP-1 dose-dependently inhibits food intake might be considered the beginning of the idea of the role of GLP-1 in appetite suppression. Subsequent studies also demonstrated that blockade of CNS GLP-1 action using ICV infusion of exendin(9-39) increased food intake and promoted weight gain in rats2. Similarly, injection of exendin(9-39) into the lateral hypothalamus increased food intake in satiated rats3.

The evidence linking GLP-1 action in the CNS to regulation of food intake and body weight has been confirmed by multiple independent laboratories. Although the PVN of the hypothalamus was the initial focus of studies linking GLP-1 actions to satiety, several studies have now demonstrated, using direct injection approaches, that multiple brain regions are capable of transducing a CNS satiety effect in response to GLP-1, including the LH, DMH, and VMH4,5.

The mechanisms transducing the anorectic actions of GLP-1R agonists appear to overlap with those activated by PYY(3-36), but distinct pathways can be identified for these 2 different types of peptides 6,7

The effects of GLP-1 and PYY, administered separately, or together, on food intake and brain activity, was assessed in healthy normal weight human subjects using functional MRI. Both GLP-1 and PYY alone reduced energy intake in fasted subjects presented with a buffet lunch, and the combination of both hormones produced an additive and significantly greater reduction in energy intake. Viewing of food intake images in the fasted state produced activation of Blood Oxygen Level Dependent (BOLD) MRI signals (assessed in food sensitive areas; amygdala, caudate, putamen, insula, nucleus acumbens, orbitofrontal cortex, and putamen). Although no significant changes were observed in the absence of food with hormone infusion, PYY alone, or PYY plus GLP-1 reduced the extent of BOLD fMRI signals generated with feeding8.

Similarly, infusion of ghrelin in rats dose-dependently attenuates the inhibitory effects of GLP-1 and exendin-4 on food intake9.


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Conversely, central or peripheral infusion of exendin-4 suppresses levels of plasma ghrelin in fasted rats. Intriguingly, the effects of exendin-4 on ghrelin secretion were not mimicked by native GLP-1, and they were not blocked by the classical GLP-1 receptor antagonist exendin(9-39). These findings implicate a role for a non-classical GLP-1R coupled to regulation of ghrelin secretion 10. Similarly infusion of GLP-1 in healthy male human subjects was associated with prevention of the postprandial decline in plasma ghrelin levels and reduced levels of ghrelin for several hours after meal ingestion. The patterns of plasma ghrelin concentrations were inversely related to the plasma levels of insulin and C-peptide, raising the possibility that the actions of GLP-1 on ghrelin may be indirect and mediated via stimulation of insulin secretion11.

Peripheral administration of long-acting GLP-1 agonists to diabetic rodents also reduced food intake and achieve weight loss in studies of several weeks duration. The Novo Nordisk GLP-1 analogue NN2211 (Liraglutide) induced weight loss in both lean control rats and in MSG-lesioned rats, hence the anorectic actions were presumably mediated by signaling systems outside the region of the hypothalamus affected by neonatal monosodium glutamate administration12.

Over a dozen human studies in both normal subjects and in patients with obesity or type 2 diabetes have examined the relationship between GLP-1 infusion and food intake13.

The majority of studies have shown a small but significant inhibition of short-term food intake with concurrent GLP-1 infusion. A meta-analysis of these studies has concluded that there is a dose-dependent reduction in food intake associated with a reduction of gastric emptying in human subjects14.

Does activation of the GLP-1 receptor produce weight loss via effects on energy expenditure? Acute administration of exendin-4 to mice inhibited food intake in association with a compensatory reduction in energy expenditure15. Similarly, administration of Liraglutide for 7 days to normal rats was associated with weight loss and a reduction in energy expenditure16. Furthermore, a 4 hour infusion of GLP-1 in 20 normal weight healthy male volunteers reduced resting energy expenditure, primarily due to lower carbohydrate oxidation with no changes in fat or protein oxidation17.

Comparable reductions in energy expenditure and carbohydrate oxidation were observed following a 4 h GLP-1 infusion in non-diabetic obese subjects studied after ingestion of a breakfast meal18. Similarly, daily administration of the GLP1R agonist Liraglutide to overweight diabetic subjects for 8 weeks was not associated with changes in body weight or 24h energy expenditure19 indicating that the weight loss is mainly associated with decreased caloric intake.

In conclusion it can be said that the use of GLP-1 analogs can decrease appetite and possibly weight independent of any changes in energy expenditure or calories burned.

To learn more about GLP-1 and Appetite Suppression please visit http://glucagon.com/glp1foodintake.html.

References:
  1. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996 4;379(6560):69-72
  2. Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat. Endocrinology. 1999 140(1):244-50.
  3. Peptides that regulate food intake: glucagon-like peptide 1-(7-36) amide acts at lateral and medial hypothalamic sites to suppress feeding in rats. Am J Physiol Regul Integr Comp Physiol. 2003 Jun;284(6):R1427-35.
  4. The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness. J Neurosci. 2002 Dec 1;22(23):10470-6.
  5. Peptides that regulate food intake: glucagon-like peptide 1-(7-36) amide acts at lateral and medial hypothalamic sites to suppress feeding in rats. Am J Physiol Regul Integr Comp Physiol. 2003 Jun;284(6):R1427-35
  6. The inhibitory effects of peripheral administration of peptide YY(3-36) and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal-brainstem-hypothalamic pathway. Brain Res. 2005 May 17;1044(1):127-31.
  7. Peripheral Exendin-4 and Peptide YY3-36 Synergistically Reduce Food Intake through Different Mechanisms in Mice. Endocrinology. 2005 Jun 2; [Epub ahead of print].
  8. The Gut Hormones PYY(3-36) and GLP-1(7-36 amide) Reduce Food Intake and Modulate Brain Activity in Appetite Centers in Humans Cell Metab. 2011 Oct 11
  9. Ghrelin Attenuates the Inhibitory Effects of Glucagon-Like Peptide-1 and Peptide YY(3-36) on Food Intake and Gastric Emptying in Rats. Diabetes. 2006 Nov;55(11):3038-46
  10. Exendin-4 potently decreases ghrelin levels in fasting rats. Diabetes. 2007 Jan;56(1):143-51
  11. Glucagon-like peptide 1 (GLP-1) suppresses ghrelin levels in humans via increased insulin secretion. Regul Pept. 2007 Mar 20; [Epub ahead of print]
  12. Systemic Administration of the Long-Acting GLP-1 Derivative NN2211 Induces Lasting and Reversible Weight Loss in Both Normal and Obese Rats. Diabetes. 2001 Nov;50 (11):2530-2539
  13. Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol. 1999 May;276(5 Pt 2):R1541-4
  14. A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans. J Clin Endocrinol Metab. 2001 86(9):4382-9
  15. Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology. 2004 Aug;127(2):546-58.
  16. Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats. Diabetes. 2001 Nov;50(11):2530-9.
  17. The effect of glucagon-like peptide-1 on energy expenditure and substrate metabolism in humans. Int J Obes Relat Metab Disord. 2000 Mar;24(3):288-98.
  18. The effect of physiological levels of glucagon-like peptide-1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int J Obes Relat Metab Disord. 2001 Jun;25(6):781-92.
  19. The effect of liraglutide, a long-acting glucagon-like peptide 1 derivative, on glycemic control, body composition, and 24-h energy expenditure in patients with type 2 diabetes. Diabetes Care. 2004 Aug;27(8):1915-21.