Tache Lab

Obesity

Gut peptide-brain interactions to modulate food intake

A number of brain and gut peptides regulate food intake. An important aspect of gut peptides is their co-release depending on the metabolic status. We were the first to identify a physiological synergistic interaction between cholecystokinin (CCK) and leptin to induce postprandial satiety in rodents. Such interaction is exerted at the levels of capsaicin-sensitive vagal afferents, resulting in the activation of specific brain nuclei. Likewise, CCK acts synergistically with the stress peptide urocortin 1 to suppress food intake through activation of gastric vagal afferents.

Alterations of Western diet-induced obesity: Beneficial effect of high protein diet

Rodents fed a Western diet containing 40% fat lost the synergistic interactions between CCK and other peptides. Dr. Lixin Wang showed that rats fed a Western diet developed increased visceral fat mass and an inflammatory response in the hypothalamus and the brain stem. Switching to a high protein diet curtailed the increase in fat mass induced by the Western diet, normalized blood glucose and restored the satiety signaling of CCK while not influencing the brain inflammation. Of importance, the study showed a correlated expansion of cecal Akkermansia muciniphila, along with a loss of fat mass induced by switching rats from a Western diet to a high-protein diet, pointing to a beneficial effect of the bacterium.

Prokinetic and orexigenic actions of ghrelin

New insight into the regulation of the gastric orexigenic hormone ghrelin was gained by our initial reports that endotoxin, the cytokine interleukin-1ß and abdominal surgery suppressed circulating ghrelin levels and food intake through distinct underlying mechanisms. Of relevance, the restoration of circulation ghrelin prevented the associated decreased gastric emptying induced by endotoxin, abdominal surgery and levodopa administration in rodents. These data may have translational applications for the use of ghrelin agonists under conditions of surgery and as an anti-Parkinsonian drug treatment associated with slow gastric transit and response fluctuations.

Approach

  • Computerized continuous monitoring of food intake
  • Body composition using the quantitative nuclear magnetic resonance analysis apparatus (Echo MRI)
  • Gut hormone plasma levels using Luminex xMAP technology for rat gut hormones
  • Model of rodent obesity

Grants

  • VA Rehab Grant. Ghrelin Agonists Multiple Beneficial Effects on Parkinson’s Non-motor Symptoms. L. Wang, PI, Y. Taché, Co-Investigator. 06/01/2015-05/31/2019
  • NIH DK-41301 Digestive Diseases Center Grant, Animal Core. Y. Taché, M. Million, L. Wang, Y. Taché, Director, M. Million, Associate Director, L. Wang, Co-Investigator. 11/01/2014-10/31/2019

Publications

  1. Wang L, Jacobs JP, Lagishetty V, Yuan PQ, Wu SV, Million M, Reeve JR Jr, Pisegna JR, Taché Y. High-protein diet improves sensitivity to cholecystokinin and shifts the cecal microbiome without altering brain inflammation in diet-induced obesity in rats. Am J Physiol Regul Integr Comp Physiol. 2017 Oct 1;313(4):R473-R486
  2. Stengel A, Taché Y. CRF and urocortin peptides as modulators of energy balance and feeding behavior during stress. Front Neurosci. 2014 Mar 18;8:52. doi: CRF and urocortin peptides as modulators of energy balance and feeding behavior during stress. Front Neurosci. 2014;8:52
  3. Stengel A, Goebel-Stengel M, Wang L, Hu E, Karasawa H, Pisegna JR, Taché Y. High-protein diet selectively reduces fat mass and improves glucose tolerance in Western-type diet-induced obese rats. Am J Physiol Regul Integr Comp Physiol. 2013 Sep 15;305(6):R582-91
  4. Barrachina MD, Martínez V, Wang L, Wei JY, Taché Y. Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in lean mice. Proc Natl Acad Sci USA. 1997 Sep 16;94(19):10455-60