Does gastric bypass surgery change body weight set point?

Abstract

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.

Figure 1

Behavioral demonstration of defense of reduced body weight level in rats with Roux-en-Y gastric (RYGB) bypass surgery. Rats that had reduced body weight after RYGB received infusion of saline or SHU9119, a potent melanocortin-4 receptor (MC4R) antagonist. MC4R blockade induced rapid weight gain to obese (sham-operated) body weight levels. After cessation of MC4R blockade body weight promptly returned to pre-infusion levels. Modified with permission from Mumphrey et al., copyright John Wiley.

Figure 2

RYGB restricts meal size but not total food intake. (a) Total daily food intake, meal size and meal frequency of RYGB rats during 14-day ICV infusion of SHU9119. (b) Meal size, meal frequency and ingestion rate of liquid formula (Ensure) of rats at 2 weeks (2w) and 20 weeks (20w) after RYGB or sham surgery. *P<0.05, RYGB vs Sham, *P<0.05, SHU9119 vs Saline. Modified with permission from Zheng et al., copyright American Physiological Association.

Figure 3

Schematic diagram showing the flow of information between the gut and the brain that is potentially important for the dynamically emerging beneficial effects of bariatric surgeries on body weight and glucose homeostasis. The primary impact of surgery leads to changes in gut structure and function that result in changes of humoral (solid gray lines and closed arrows) and neural (broken black lines and open arrows) signaling within the gut itself and to the brain and other organs such as liver, muscle, pancreas, white (WAT) and brown (BAT) adipose tissue. The secondary impact of surgery on these ‘other’ organs changes their signaling to the brain and back to the gut via humoral and neural mechanisms. The brain integrates humoral and neural signals from gut and other organs and orchestrates adaptive behavior and metabolic control through changes in eating behavior and autonomic/endocrine outflow (A & E outflow). Abbreviation: ENS, enteric nervous system.

Figure 4

Partial attenuation of body weight-lowering effects of RYGB in leptin-deficient ob/ob mice. (a) Effect of RYGB (filled symbols) and sham surgery (open symbols) on body weight in genetically (ob/ob, circles) and diet-induced (triangles) obese mice. (b) Leptin treatment (daily injections of 1 mg kg⁻¹, i.p.) reduces body weight and food intake (inset) more in ob/ob mice with RYGB compared with sham surgery. *P<0.05, RYGB vs sham. Modified with permission from Hao et al.

Figure 5

RYGB does not restore two measures of leptin sensitivity in mice. (a, b) Effect of 4-day leptin treatment (daily injections of 1 mg kg⁻¹, i.p.) on suppression of food intake and body weight in non-surgical mice fed chow (lean controls) and mice with RYGB or sham surgery fed high-fat (60% energy) diet. *P<0.05 vs chow. (c) Serum leptin levels of non-surgical mice fed chow and mice with RYGB or sham surgery and non-surgical mice weight-matched to RYGB, all fed high-fat diet. *P<0.05 vs chow. (d) Leptin-induced (1 mg kg⁻¹, i.p.) phosho-STAT3 expression in basomedial hypothalamus in non-surgical mice fed chow and mice with RYGB or sham surgery and non-surgical mice weight-matched to RYGB, all fed high-fat diet.