Eating in mice with gastric bypass surgery causes exaggerated activation of brainstem anorexia circuit.

BACKGROUND/OBJECTIVE: Obesity and metabolic diseases are at an alarming level globally and increasingly affect children and adolescents. Gastric bypass and other bariatric surgeries have proven remarkably successful and are increasingly performed worldwide. Reduced desire to eat and changes in eating behavior and food choice account for most of the initial weight loss and diabetes remission after surgery, but the underlying mechanisms of altered gut-brain communication are unknown. SUBJECTS/METHODS: To explore the potential involvement of a powerful brainstem anorexia pathway centered around the lateral parabrachial nucleus (lPBN), we measured meal-induced neuronal activation by means of c-Fos immunohistochemistry in a new high-fat diet-induced obese mouse model of Roux-en-Y gastric bypass (RYGB) at 10 and 40 days after RYGB or sham surgery. RESULTS: Voluntary ingestion of a meal 10 days after RYGB, but not after sham surgery, strongly and selectively activates calcitonin gene-related peptide neurons in the external lPBN as well as neurons in the nucleus tractus solitarius, area postrema and medial amygdala. At 40 days after surgery, meal-induced activation in all these areas was greatly diminished and did not reach statistical significance. CONCLUSIONS: The neural activation pattern and dynamics suggest a role of the brainstem anorexia pathway in the early effects of RYGB on meal size and food intake that may lead to adaptive neural and behavioral changes involved in the control of food intake and body weight at a lower level. However, selective inhibition of this pathway will be required for a more causal implication.

Does gastric bypass surgery change body weight set point?

The relatively stable body weight during adulthood is attributed to a homeostatic regulatory mechanism residing in the brain which uses feedback from the body to control energy intake and expenditure. This mechanism guarantees that if perturbed up or down by design, body weight will return to pre-perturbation levels, defined as the defended level or set point. The fact that weight re-gain is common after dieting suggests that obese subjects defend a higher level of body weight. Thus, the set point for body weight is flexible and likely determined by the complex interaction of genetic, epigenetic and environmental factors. Unlike dieting, bariatric surgery does a much better job in producing sustained suppression of food intake and body weight, and an intensive search for the underlying mechanisms has started. Although one explanation for this lasting effect of particularly Roux-en-Y gastric bypass surgery (RYGB) is simple physical restriction due to the invasive surgery, a more exciting explanation is that the surgery physiologically reprograms the body weight defense mechanism. In this non-systematic review, we present behavioral evidence from our own and other studies that defended body weight is lowered after RYGB and sleeve gastrectomy. After these surgeries, rodents return to their preferred lower body weight if over- or underfed for a period of time, and the ability to drastically increase food intake during the anabolic phase strongly argues against the physical restriction hypothesis. However, the underlying mechanisms remain obscure. Although the mechanism involves central leptin and melanocortin signaling pathways, other peripheral signals such as gut hormones and their neural effector pathways likely contribute. Future research using both targeted and non-targeted 'omics' techniques in both humans and rodents as well as modern, genetically targeted, neuronal manipulation techniques in rodents will be necessary.

Roux-en-Y gastric bypass surgery increases number but not density of CCK-, GLP-1-, 5-HT-, and neurotensin-expressing enteroendocrine cells in rats.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is very effective in reducing excess body weight and improving glucose homeostasis in obese subjects. Changes in the pattern of gut hormone secretion are thought to play a major role, but the mechanisms leading to both changed hormone secretion and beneficial effects remain unclear. Specifically, it is not clear whether changes in the number of hormone-secreting enteroendocrine cells, or changes in the releasing stimuli, or both, are important. METHODS: We estimated numbers of enteroendocrine cells after immunohistochemical staining in fixed tissue samples from rats at 10-11 months after RYGB. KEY RESULTS: Numbers of glucagon-like peptide-1 (GLP-1) (L-cells, co-expressing peptide YY (PYY)), cholecystokinin (CCK), neurotensin, and 5-HT-immunoreactive cells were significantly increased in the Roux and common limbs, but not the biliopancreatic limb in RYGB rats compared with sham-operated, obese rats fed high-fat diet, and chow-fed controls. This increase was mostly accounted for by general hyperplasia of all intestinal wall layers of the nutrient-perfused Roux and common limbs, and less to increased density of expression. The number of ghrelin cells in the bypassed stomach was not different among the three groups. CONCLUSIONS & INFERENCES: The findings suggest that the number of enteroendocrine cells increases passively as the gut adapts, and that the increased total number of L- and I-cells is likely to contribute to the higher circulating levels of GLP-1, PYY, and CCK, potentially leading to suppression of food intake and stimulation of insulin secretion. Whether changes in releasing stimuli also contribute to altered circulating levels will have to be determined in future studies.