Hormone Changes After Weight-Loss Surgery in People with Obesity

Gastrin is a peptide hormone (34 amino acids) that stimulates parietal cells in the stomach to secrete gastric acid and is involved in gastric motility [24,25]. Secreted by G cells located in the duodenum, pancreas, and pyloric antrum of the stomach, gastrin promotes the release of histamines from enterochromaffin-like cells by binding to CCK B receptors. It also facilitates the insertion of K+/H+ ATPase pumps into the apical membrane of parietal cells, thereby enhancing hydrogen ion secretion into the stomach lumen. The release of gastrin is triggered by the presence of peptides in the stomach, and it also plays a role in appetite suppression. Importantly, gastrin is not a single molecular entity but rather a family of peptides with varying lengths and biological activities [24,25].

Several studies have investigated the complex physiological and hormonal changes following MBS such as RYGB and SG, demonstrating that postprandial gastrin levels typically decrease after RYGB, both in the early two weeks and throughout the first-year post-operation [26,27]. A study [28] demonstrated that individuals with stomal ulcers post-RYGB experienced significantly elevated gastric acid exposure, with a median of 69% of the time with pH below 4, compared to 20% in controls. These findings implicate acid exposure as a potential factor in ulcer formation, independent of fistula presence [28]. Another prospective study [29] assessed the effects of laparoscopic AGB, showing an average excess weight loss of 45.7% over 12 months, accompanied by a sharp decrease in leptin levels from 19.7 ng/mL to 6.9 ng/mL (p < 0.001). Despite weight loss, hormones like ghrelin, PP, insulin, GIP, GLP-1, gastrin, and pepsinogen I remained stable, with only transient changes in pepsinogen II, indicating preservation of overall gastrointestinal endocrine function [29].

Research [30] comparing gastrin secretion and metabolic responses found that RYGB was associated with significantly lower serum gastrin levels and reduced glucose area under the curve (AUC) during meal testing (p = 0.013), implying altered hormonal regulation and enhanced glycemic control. In contrast, SG showed a trend toward increased gastrin secretion without reaching statistical significance (p = 0.091), and neither procedure caused hypergastrinemia. These variations highlight that the type of MBS differentially impacts gastric hormone secretion and mucosal function [30]. Finally, histological analysis [31] of the excluded stomach after RYGB revealed increased cell proliferation (higher ki-67 index) and decreased apoptosis (lower caspase-3 expression), along with a significant reduction in gastrin-positive cells (29.6 ± 7.9 vs. 55.5 ± 11.7; p = 0.0003). These findings suggest active mucosal remodeling, through increased proliferation and decreased programmed cell death, which may influence long-term gastric mucosal integrity [31]. Biomarker studies [32] further indicated that 80% of SG individuals had low protein glycation index (PGI) levels (<30 µg/L), a marker of gastric atrophy, mainly affecting the fundic mucosa. These individuals also exhibited elevated fasting G17 levels (13.9 ± 17.2 pmol/L), with 40% exceeding the normal upper limit, reflecting the impaired acid-secreting capacity of the stomach's fundic region [32].

These studies collectively demonstrate that MBS induces significant structural, hormonal, and functional changes within the gastrointestinal tract. RYGB tends to elevate gastric acid exposure, promote mucosal remodeling, and decrease gastrin secretion, while SG more profoundly impairs fundic gland function and acid secretion, as reflected by low PGI and elevated G17 levels. Understanding these alterations is important for optimizing postoperative management, predicting long-term risks, and tailoring treatment strategies to ensure patient safety and effective metabolic outcomes.

A 28-amino acid peptide that is mostly secreted in the stomach, ghrelin promotes the release of growth hormone (GH) and appetite [33,34]. The word "ghre," which means "grow" in Proto-Indo-European languages, is the root of the name "ghrelin," referring to its capacity to promote the release of growth hormone. Although ghrelin was first identified as a stomach-derived hormone that acts through hypothalamic circuits to regulate energy balance, hunger, and meal initiation, it is now evident that it also plays a part in motivated reward-driven behaviors by activating the so-called "cholinergic–dopaminergic reward link". This reward link consists of a cholinergic input that originates mainly from the laterodorsal tegmental area and a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens. The cholinergic–dopaminergic reward link is activated when ghrelin is administered into the VTA, which implies that ghrelin may raise the incentive value of motivated behaviors like reward-seeking behavior (also known as "wanting" or "incentive motivation") [33,34].

Furthermore, mice and rats that receive ghrelin injections directly into their brain ventricles or the VTA consume more alcohol and rewarding foods [35]. Ghrelin receptor antagonists have been shown in rodent studies to have positive effects on reducing the intake of palatable foods, decreasing calorie-dense food preferences, and suppressing food reward and food-motivated behavior. Additionally, they have been demonstrated to lower alcohol intake and inhibit amphetamine-, cocaine-, and alcohol-induced rewards. Additionally, changes in the ghrelin receptor and pro-ghrelin genes have been linked to obesity, bulimia nervosa, smoking, heavy alcohol use, and increased weight gain in alcohol-dependent people. Therefore, the central ghrelin signaling system connects neurobiological circuits involved in food and chemical drug reward; substances that either directly or indirectly inhibit this system become promising candidate medications for treating substance use disorders and preventing problematic overeating that results in obesity [33,34].

In humans, several studies have investigated how MBS affects ghrelin levels and weight regulation. One study [36] observed that in individuals with obesity following a dietary regimen, plasma ghrelin levels increased significantly during the 24-h cycle, especially before meals, and the AUC for ghrelin increased by 24% as body weight decreased by 17% (p = 0.006). Conversely, in RYGB individuals, ghrelin levels were 77% lower than in controls and 72% lower than in matched controls with obesity, despite a 36% weight loss, with no normal food-related diurnal fluctuations, indicating a lasting suppression of ghrelin secretion linked to the surgical bypass of ghrelin-producing cells in the fundus [36]. Another study [37] compared weight loss induced by AGB, RYGB, and dietary treatment in 24 matched men, finding that only RYGB caused a significant decrease in fasting plasma ghrelin concentrations (from 424.6 ± 32.8 pg/mL to 131.4 ± 13.5 pg/mL; p < 0.001), despite similar weight loss across groups. Notably, even in individuals who underwent total gastrectomy, which completely removes ghrelin-producing tissue, ghrelin levels remained low, indicating that RYGB's reduction in ghrelin is due to bypassing the fundus rather than a secondary effect of weight loss or improved insulin sensitivity [37].

A further comparison study [36] involving individuals who achieved comparable weight loss through AGB, RYGB, or biliopancreatic diversion showed that RYGB individuals had significantly lower fasting plasma ghrelin levels (average 117 ± 34 pg/mL) compared to both banding (480 ± 78 pg/mL) and BPD (406 ± 86 pg/mL), with no significant differences in BMI, fat mass, or metabolic markers. This suggests that the degree of fundus bypass or removal directly influences ghrelin secretion, with RYGB producing a more substantial suppression due to the anatomical disruption of the ghrelin-producing cells [38]. A systematic review and meta-analysis of 7 studies assessing the impact of SG on ghrelin levels also showed that SG leads to a reduction in ghrelin levels [39]. A study examined long-term hormonal responses in patients more than seven years after SG and BPD/RYGB dividing them into groups based on weight maintenance or regain [40]. The results showed that fasting levels of ghrelin, GLP-1, and PYY did not differ significantly between groups, and postprandial hormone responses largely remained similar. Notably, SG patients in the weight-maintaining group experienced greater suppression of ghrelin after a meal, while post-meal PYY levels were lower in the weight-maintenance group regardless of surgery type. Interestingly, higher PYY levels correlated with increased BMI, suggesting that these hormonal patterns are more reflective of ongoing weight changes, rather than being primary causes of weight regain. Overall, the data do not support the hypothesis that long-term weight regain is due to unfavorable gastrointestinal hormone secretion, highlighting the complexity of the factors involved in weight maintenance after bariatric surgery [40].

A literature review using PubMed and Google Scholar examined the impact of metabolic surgeries, especially gastric fundus resection via SG and modified laparoscopic gastric bypass with fundus resection (RYGB), on ghrelin levels and glucose regulation [41]. Of the numerous studies, 14 human investigations met the inclusion criteria. The findings indicate that reduced ghrelin levels after fundus resection may help early glycemic improvements, often before significant weight loss. However, long-term evidence on ghrelin's role in glucose homeostasis is limited and inconclusive, highlighting the need for further research [41].

Collectively, these studies highlight that MBS involving bypass or removal of the gastric fundus significantly reduces circulating ghrelin levels, independent of weight loss or metabolic improvements. This suppression of ghrelin likely contributes importantly to decreased appetite and sustained weight loss, reinforcing the idea that anatomical disruption of ghrelin-producing cells plays a crucial role in the long-term success of certain bariatric procedures.

Several mammals, including humans, have specialized epithelial cells in their stomachs and small intestines that produce the hormone obestatin (23 amino acids) [42,43,44]. Though its impact on food intake is still debatable, obestatin was first discovered to be an anorectic peptide. The same gene that produces the peptide hormone ghrelin also encodes the hormone obestatin. Ghrelin breaks down into proghrelin, which breaks down into unacylated ghrelin (28 amino acids) and acylated ghrelin. Presumably, obestatin is cleaved from C-ghrelin [42,43,44]. Limited research has examined the role of obestatin in obesity and sustained weight management. One study [45] reported that subjects with severe obesity had significantly lower fasting obestatin levels compared to lean controls (17.2 ± 2 vs. 27.8 ± 4 pg/mL, p = 0.03). Individuals who underwent gastrectomy showed a decrease in obestatin levels, though it was not statistically significant, and the obestatin/ghrelin ratio was higher in gastrectomy individuals (0.05 ± 0.009) than in lean and controls with obesity, indicating altered hormone balance. The study also noted that meal intake did not significantly change obestatin levels, suggesting that obestatin secretion remains stable after eating and may originate from sources outside the stomach [45]. Another investigation [46] evaluated ghrelin and obestatin in individuals with obesity who achieved long-term weight loss through either RYGB or lifestyle intervention. The results showed that RYGB individuals had higher fasting levels of both ghrelin and obestatin compared to preoperative controls, whereas the lifestyle group did not. Post-meal suppression of ghrelin was observed in all groups, but obestatin levels did not change significantly during the postprandial period. However, the ghrelin/obestatin ratio remained similar across all groups, suggesting that these hormones are regulated independently post-surgery [46].

Overall, in terms of appetite regulation, obestatin behaves in the opposite way compared to ghrelin, and thus far the evidence indicates that plasma obestatin levels are lower in individuals with obesity compared to lean controls, supporting a potential role in long-term body weight regulation. Obestatin levels tend to decrease following gastrectomy, which may influence appetite and energy balance beyond gastric hormonal production.

Pancreatic islet β-cells synthesize insulin, a 51-amino-acid peptide hormone that plays a central role in regulating protein, fat, and carbohydrate metabolism by promoting glucose uptake, particularly in skeletal muscle, liver, and adipose tissue [26,47].

Several studies have investigated how MBS improves glucose metabolism and hormonal responses related to T2D. One study [48] assessed the early and late effects of MBS on insulin sensitivity and β-cell function. 35 individuals with T2D (23 RYGB, 12 SG) were studied undergoing mixed-meal testing before, 15 days after, and one-year post-surgery. The results showed long-term improvements in insulin sensitivity, which is closely linked to weight loss (p < 0.001), while β-cell glucose sensitivity improved both early and late after surgery (p < 0.005). Meal responses showed decreased pancreatic polypeptide (PP) in the early post-RYGB period, increased glucagon and GLP-1 at both time points, and elevated PYY at one year. Preoperative β-cell sensitivity and meal-stimulated GLP-1 responses predicted T2D remission [48]. A second study [49] assessed 12 T2D and 15 non-diabetic subjects with obesity before and one year after surgery using mixed-meal testing with double-tracer techniques. Postoperatively, glucose and insulin levels declined sharply, and insulin sensitivity improved with approximately 30% weight loss. β-cell glucose sensitivity doubled but remained below normal, indicating partial recovery. The rapid decline in plasma glucose and insulin, along with relative hyperglucagonemia, led to less suppressed endogenous glucose production during the meal, highlighting altered glucose regulation primarily driven by bypass surgery affecting hormonal responses [49].

Another study followed 10 T2D and 10 glucose-tolerant individuals with obesity pre- and post-RYGB at 1 week, 3 months, and 1 year [50]. Early after surgery, basal hepatic glucose production decreased, hepatic insulin sensitivity improved, and insulin clearance increased significantly, especially in T2D individuals, pointing to early liver adaptations. Later, peripheral insulin uptake and secretion improved, particularly in response to oral glucose, emphasizing that gut anatomy changes predominantly modulate postprandial insulin responses and glucose disposal [50]. A further study tracked 20 individuals after SG at 7, 30, and 90 days [51]. Subjects exhibited rapid reductions in BMI, insulin, and HOMA-IR, indicating swift improvements in insulin sensitivity. Early declines in fasting glucose and insulin levels correlated with weight loss, highlighting the rapid metabolic benefits that precede full weight stabilization [51]. Lastly, a comprehensive study compared three surgical procedures and dietary intervention over three years. All surgical groups exhibited significant and sustained decreases in HOMA-IR, with increases in PYY and adiponectin during the weight stability phase [52]. These hormones contributed to ongoing insulin sensitivity improvements independent of weight, suggesting that hormonal shifts post-surgery play a key role in long-term metabolic health [52].

Overall, MBS induces rapid and durable improvements in β-cell function, insulin sensitivity, and hormonal regulation, driven by anatomical changes affecting gut hormone secretion and liver function. Early adaptations in the liver and hormonal responses are crucial for achieving and maintaining diabetes remission and metabolic health.

Alpha cells of the pancreatic islets of Langerhans, which are found in the endocrine section of the pancreas, produce the 29-amino acid peptide hormone, known as glucagon [53,54]. Insulin from the nearby β-cells suppresses or regulates its production. By encouraging glycogenolysis and gluconeogenesis, glucagon, which is also released during fasting, raises blood sugar levels [53,54]. The impact of MBS on circulating glucagon levels has been evaluated in relatively few studies.

A study examined the early effects of RYGB on hormonal and metabolic parameters in individuals with T2D [55]. Prior to and after RYGB, 10 individuals (BMI: 39.7 ± 1.9 kg/m²) underwent assessments, including plasma measurements of insulin, glucose, glucagon, and GLP-1, alongside a meal test. Notably, seven days post-surgery, the HOMA-IR index significantly decreased from 7.8 ± 5.5 to 2.6 ± 1.7, with a modest, non-significant weight reduction (p < 0.05). Hormonal responses showed that glucagon and glucose levels gradually declined during the meal, while insulin and GLP-1 peaked at 30 min. These changes persisted and intensified over time, with improvements in β-cell function and a positive correlation between insulin and GLP-1 levels (p = 0.000). Overall, RYGB appears to induce early hormonal adaptations that support improved glycemic control beyond weight loss [55]. In a separate study, Farey et al. investigated the effects of SG on fasting hormonal levels and non-esterified fatty acids (NEFA) in individuals with obesity, comparing the results to non-obese controls [56]. Using multiplex bead-based assays, nine hormones and NEFA were measured at baseline and three months post-operation in 11 individuals. Individuals with obesity exhibited lower ghrelin, GIP, and resistin, but higher C-peptide, insulin, and leptin compared to controls. Post-SG, BMI decreased from 42.5 ± 6.47 to 35.2 ± 5.14 kg/m² (42% excess weight loss, p < 0.001), with significant declines in ghrelin, GLP-1, glucagon, leptin, PAI-1, and NEFA. These early hormonal shifts suggest that SG influences key regulators of obesity and metabolic health, though mechanisms may differ from other bariatric procedures with malabsorptive components [56].

As post-prandial hypoglycemia (PPHG) is a common adverse effect in individuals undergoing MBS [57,58] research has also been conducted to assess the hormonal changes following PPHG. In a recent case-control study, 24 individuals with pre-operation T2D who underwent RYGB were studied; half of them developed PPPHG following operation [59]. It was shown that individuals who developed PPHG had enhanced glucose clearance, due to higher insulin sensitivity and early hyperinsulinemia. Importantly, individuals with PPHG had a defective glucagon response, which prevented an increase in endogenous glucose production to prevent the hypoglycemic event [59].

The hormonal changes observed post-surgery, including alterations in glucagon, contribute to improved glycemic control and metabolic health. These findings underscore the importance of glucagon in the complex hormonal adaptations induced by MBS, supporting its role in the successful management of obesity and T2D.

SS is a peptide hormone that plays a pivotal role in regulating the endocrine system by inhibiting the release of various secondary hormones. It interacts with G protein-coupled SS receptors, influencing neurotransmission and cell proliferation [60,61]. In the pancreas, stomach, and duodenum, delta cells produce SS, which exists in two biologically active forms, 14 and 28 amino acids long, resulting from the cleavage of a pre-prohormone at distinct sites. In addition to its role in the central nervous system, SS has significant effects within the gastrointestinal tract and other endocrine organs. Specifically, SS reduces the secretion of key gastrointestinal hormones, including gastrin, secretin, CCK, GIP, and GLP-1. In the pituitary gland, it suppresses the secretion of prolactin, thyroid-stimulating hormone, and growth hormone. Additionally, in the pancreas, SS inhibits exocrine secretion and reduces the production and release of glucagon and insulin. In preclinical studies involving rats on a high-fat diet, the SS analogue octreotide, which shows a high binding affinity for SS receptor 2 and a lower affinity for receptors 3 and 5, has been observed to decrease adiposity [60,61]. However, the role of SS following MBS remains inadequately characterized in humans, with current knowledge primarily derived from preclinical data [62]. Further research is warranted to elucidate its function and therapeutic potential in the context of bariatric interventions.

PP is a polypeptide expressed primarily in the head of the pancreas by PP cells in the endocrine pancreas [63]. It has 36 amino acids. In addition to its effects on hepatic glycogen levels and gastrointestinal secretions, PP self-regulates the endocrine and exocrine secretion activities of the pancreas. Its secretion is lowered by SS and intravenous glucose, and it is elevated in humans following a protein meal, fasting, exercise, and acute hypoglycemia [63].

A study by Dixon et al. assessed whether the structurally related satiety hormones PYY and PP affected the overall percentage of weight loss following AGB [64]. A cross-sectional study looked at 17 postoperative individuals who had already lost an average of 28% of their body weight due to laparoscopic AGB. Prior to laparoscopic AGB, 16 people with obesity participated in a prospective study that evaluated their plasma PP and PYY meal responses. Higher weight loss was associated with lower fasting PYY levels (p = 0.02) and lower PP meal responses (p = 0.01). After an average of 53 months, the prospective study found that the subsequent mean weight loss was 20%. Significantly greater weight loss after AGB was predicted by a low preoperative PP meal response (2 h area under the curve (AUC)) (p = 0.024). Eight people who responded to PP meals the least lost more weight than eight who responded to PP meals the most (median 25% vs. 14%, p = 0.004). The mean PP meal responses were the same for all three groups. However, compared to the pre-operative group or the BMI-matched controls, the postoperative group's fasting PYY levels were significantly lower (p = 0.03). After AGB, PYY seems to decrease proportionately to weight loss, which could indicate an attempt at orexigenic homeostatic compensation. Low PP meal response may indicate greater weight loss, even though PP responses seem to be unaffected by weight loss status. A person's susceptibility to the mechanism of AGB-induced weight loss may be predicted by their PP meal response, a biological marker [64].

VIP is a 28-amino acid neuropeptide and neurotransmitter that is broadly distributed throughout the central and peripheral nervous systems [65]. Both neurons and immune cells synthesize and release VIP, which interacts with specific receptors expressed on immune and various other cell types. VIP exhibits a diverse range of biological effects, acting as a neurotransmitter, vasodilator, secretagogue, and immune regulator [65]. A study assessed the impact of RYGB on the metabolic response to orally administered glucose, specifically examining levels of glucose, insulin, VIP, neurotensin, and motilin in eight morbidly individuals with obesity, both pre- and postoperatively [66]. Prior to the surgery, an oral glucose tolerance test (OGTT) demonstrated hyperinsulinism and glucose intolerance in all individuals who remained asymptomatic throughout the test. Notably, the plasma levels of VIP, neurotensin, and motilin were undetectable during this initial assessment. However, three months post-RYGB, after an average 21% weight loss, all individuals experienced acute symptoms during repeat OGTT, including facial flushing, palpitations, nausea, abdominal fullness, pallor, diaphoresis, vomiting, and diarrhea. Importantly, three of the eight individuals exhibited an elevated release of VIP, while seven showed a significant increase in neurotensin levels. These findings suggest that the hormonal changes associated with RYGB may be linked to the pathophysiology of dumping syndrome, underscoring the role of VIP and neurotensin in postoperative metabolic responses [66]. In conclusion, this study highlights the significant hormonal shifts that occur after RYGB, contributing to the understanding of metabolic adaptations and potential complications such as dumping syndrome in individuals with obesity.

GLP-1 is a peptide hormone with 30 amino acids that is produced when the proglucagon gene undergoes tissue-specific posttranslational processing [67,68]. After eating, it is created and released by intestinal enteroendocrine L-cells and specific neurons in the brain stem's solitary tract nucleus. GLP-1 is the only incretin known to have the capacity to lower blood sugar levels in a glucose-dependent manner by increasing insulin secretion, in addition to GIP [67,68]. GLP-1 has been linked to a variety of regulatory and protective effects in addition to its insulinotropic effects [69,70,71,72]. However, a common observation following MBS in both humans and animal models is the sharp increase in a number of gut peptides, such as satiety GLP-1, after meals. Weight loss and improvements in glucose metabolism following surgery have been attributed primarily to an increase in endogenous GLP-1 signaling. But there is ongoing discussion about how much GLP-1 and other gut peptides contribute to the metabolic improvements following MBS [69,70,71,72].

Following RYGB, individuals with T2D experience improved β-cell function primarily driven by increased GLP-1 secretion. A study by Jørgensen and colleagues [73] showed that after surgery, GLP-1 levels and β-cell glucose sensitivity doubled. Using the GLP-1 receptor antagonist exendin (9–39), they found that, before surgery, blocking GLP-1R had no effect, but after RYGB, blockade reduced glucose tolerance and normalized β-cell sensitivity, emphasizing GLP-1's critical role in metabolic improvements [73]. Another study revealed that RYGB raised post-meal GLP-1 levels over three times higher than AGB and controls, correlating with increased insulin secretion and lower glucose. This indicates that an enhanced incretin response underpins better glucose regulation and weight loss [74]. A third study examined islet responsiveness and found that RYGB increased postprandial GLP-1 and insulin secretion and improved insulin sensitivity at 1 week and 3 months [75]. Despite hormonal changes, responses to intravenous GIP and GLP-1 remained unchanged, but OGTT showed paradoxical glucagon rise and decreased 2-h glucose, linking hormonal adaptations with improved glycemic control [75]. These findings highlight that RYGB enhances endogenous GLP-1 secretion and β-cell responsiveness, which play a central role in improving glucose homeostasis and promoting remission of T2D.

GLP-2 is a 33-amino acid peptide that is generated from the posttranslational proteolytic cleavage of proglucagon, a process that also produces GLP-1 [76,77]. GLP-2 is synthesized by intestinal endocrine L cells and numerous neurons in the central nervous system, and both GLP-2 and GLP-1 are co-secreted in response to nutrient ingestion [76,77]. A study aimed to investigate the relationship between satiety regulation after RYGB and the levels of GLP-1 and GLP-2 [78]. Eleven participants who had undergone RYGB were monitored over the course of one year. Satiety was assessed using a visual analogue scale (VAS) to correlate scores with the levels of GLP-1 and GLP-2 measured pre- and post-surgery. The results indicated a significant increase in the AUC for GLP-2 following the standard meal tolerance test, from 945.3 ± 449.1 to 1787.9 ± 602.7 (p = 0.0037). Notably, post-surgery, the AUC for GLP-1 showed a significant negative correlation with the VAS response to the question "How hungry do you feel?" (p = 0.008). In contrast, the AUC for GLP-2 demonstrated a significant positive correlation with the mean scores for two additional VAS questions: "How full do you feel?" and "How much do you think you can eat?" (p = 0.005 and p = 0.042, respectively). These findings suggest that both GLP-1 and GLP-2 are significantly associated with satiety assessment in this sample of individuals following RYGB, providing insight into the hormonal mechanisms underlying appetite regulation after MBS [78].

Another gastrointestinal peptide hormone, CCK plays crucial roles in metabolic physiology, maintaining a healthy nutritional state, and possibly preventing and treating obesity, which is currently one of the leading causes of direct or indirect morbidity and mortality [79]. A comparative study of RYGB and SG over one year in non-diabetic individuals showed that both procedures resulted in significant weight loss and improved insulin sensitivity [80]. Post-surgery, both groups had increased postprandial GLP-1 and PYY levels, contributing to improved glucose control. RYGB ghrelin levels returned to preoperative values by 12 months, restoring normal fluctuations, while SG individuals maintained suppressed ghrelin levels. CCK responses differed: they increased less after RYGB but were significantly higher in SG, indicating different hormonal adaptations beyond the anatomical bypass effects [80]. Another study [81] investigated factors affecting weight loss responses after RYGB. Good responders displayed greater GLP-1 secretion, more ghrelin suppression, and reduced hunger during meals, while poor responders had higher CCK secretion and less favorable hormone responses. Exaggerated gut hormone release correlated with better weight loss, emphasizing the role of hormonal regulation in surgical success [81]. A third study assessed SG's effects on hormone responses, appetite, and gastric motility. The results showed that SG individuals had lower fasting ghrelin, faster gastric emptying, and higher postprandial GLP-1 and CCK levels, leading to increased satiety and reduced hunger. These hormonal shifts, along with improved insulin sensitivity, likely drive weight loss and better glucose control post-SG [82]. These data demonstrate that hormonal changes, including decreased ghrelin, increased GLP-1 and CCK, and altered gastric emptying, are central to weight loss and metabolic improvements following MBS [82]. Understanding these hormone dynamics is key to optimizing treatment outcomes.

In humans, the gene encoding PYY, also known as PYY3-36, has been extensively studied for its role in appetite regulation [83,84,85]. PYY is a 36-amino acid peptide secreted by L enteroendocrine cells located in the distal small intestine and colon in response to food intake. After its release, PYY1–36 is rapidly converted to PYY3–36 in the bloodstream by the enzyme dipeptidylpeptidase-IV (DPP-IV). PYY3–36 is believed to enhance feelings of satiety by activating the Y2 receptor in the brain. The effects of PYY3–36 are multifaceted; it is known to slow gastric emptying, decrease postprandial insulin secretion, and modulate colonic motility. However, its primary role appears to be the central regulation of appetite [83,84,85]. Research conducted by Le Roux et al. demonstrated that individuals with obesity exhibit significantly lower postprandial levels of PYY3–36 compared to those of normal weight. Furthermore, studies have shown that infusion of PYY3–36 leads to reduced food intake in participants, suggesting that enhancing PYY signaling could have therapeutic implications for appetite control and weight management [86]. In summary, PYY3–36 plays an essential role in mediating satiety and appetite regulation, with potential applications in the treatment of obesity and related metabolic disorders. Understanding the mechanisms governing PYY secretion and action may offer new avenues for therapeutic interventions aimed at improving appetite control.

OXM originates from the proglucagon gene through alternative posttranslational processing pathways [87]. It is a naturally occurring 37-amino acid peptide structurally similar to glucagon, with an additional C-terminal octapeptide [88]. OXM is produced by the L cells in the colon and has been found to suppress appetite. Glucagon receptors and GLP1 receptors are activated by OXM, exhibiting a more dynamic range of effects that are more likely to correspond with changing health gain objectives in the treatment of obesity [88]. Data indicate that gut hormones significantly contribute to the metabolic improvements seen after MBS. One study [89] found that RYGB enhances the OXM response to glucose, more than doubling its levels post-meal, and this increase correlates with higher GLP-1 and PYY levels. These changes occur early and are independent of weight loss, suggesting that gut hormone reprogramming drives improved glucose homeostasis, glucose tolerance, and appetite regulation [89]. Another study observed that, within days after RYGB, there were increased postprandial levels of GLP-1, OXM, and insulin sensitivity, alongside a decrease in fasting glucose, reduced insulin resistance, and improved satiety. Over two months, the amino acid and glucose absorption reflected these hormonal shifts, with faster gastric emptying and greater insulin efficiency supporting better glucose control and weight loss [90]. A long-term study tracked RYGB and SG individuals over 10 years. The results showed sustained weight loss, increased lean muscle mass, and continued improvements in metabolic, cardiovascular, and lipoprotein profiles. Notably, SG individuals maintained lower ghrelin levels, while RYGB resulted in increased secretion of proglucagon-derived peptides like glicentin and OXM. The persistent hormonal changes, especially in gut-derived hormones, underpin the enduring health benefits seen long after surgery, including reduced cardiometabolic risk and stable weight management [91]. The evidence suggests that alterations in gut hormones, particularly increased GLP-1, OXM, and PYY, along with suppressed ghrelin, are fundamental to the long-term weight loss, improved glucose regulation, and cardiovascular health observed after MBS. These hormonal shifts are critical mechanisms driving durable metabolic benefits.

GIP is derived from a 153-amino acid proprotein encoded by the GIP gene and circulates as a biologically active 42-amino acid peptide [92,93]. GIP, a substance with similar effects to GLP-1, is produced by K cells situated within the mucosa of the duodenum and jejunum in the digestive system. Consumption of oral glucose triggers a response, often referred to as the incretin effect, which involves an increase in insulin secretion [92,93]. A study aimed to clarify the mechanisms underlying diabetes reversibility following malabsorptive MBS [94]. Nine individuals with obesity and T2D had their peripheral insulin sensitivity and β-cell function evaluated before and one month after biliopancreatic diversion using minimal model analysis and either intravenous (IVGTT) or OGTT tests. The results were compared to those of six normal-weight control subjects. GIP, GLP-1, and the euglycemic clamp were used to measure insulin-dependent whole-body glucose disposal. Following the procedure, the IVGTT's initial phase of insulin secretion completely returned to normal. The disposition index from IVGTT data increased roughly 3.5 times, as was the case following the euglycemic clamp, and the disposition index from OGTT data increased roughly 10 times, becoming comparable to the values observed in the control subjects. For GIP, the AUC dropped by approximately four times, p < 0.05. The AUC for GLP1 nearly tripled, p < 0.001. Changes in GIP or GLP1% and adjustments to the sensitivity indices, regardless of the glucose administration route, did not correlate significantly. In individuals with T2D, the restoration of first-phase insulin secretion and normalization of insulin sensitivity following malabsorptive MBS appears to be associated with a decrease in the impact of some intestinal factors or factors brought on by intestinal bypass [94].

Researchers assessed early alterations in insulin physiology, gut hormone responses, and glycemia after AGB or RYGB surgery using an easily tolerated, slowly ingested solid, low-carbohydrate MMT in a prospective non-randomized study [95]. In individuals who were metabolically healthy and with obesity (gastric banding = 8 or RYGB = 10), the MMT responses of plasma glucose, insulin, and c-peptide (to estimate hepatic insulin extraction; %HIE), incretins (GIP, aGLP-1), and PP were assessed 4–8 weeks prior to and following surgery. There was no change in %HIE (p = 0.98) after gastric banding surgery, but the C-peptide and insulin MMT profiles (p = 0.004 and p = 0.0005, respectively) were lower. The prandial aGLP-1 responses' trajectory was changed by RYGB (treatment × trajectory p = 0.02), and PP was decreased (p < 0.0001). The response patterns of plasma glucose, insulin, and gut hormones to a solid, slowly ingested low-carbohydrate MMT are significantly different after RYGB than after AGB. Glycemia improved more quickly following RYGB than following AGB, which is consistent with altered nutrient delivery and indirect evidence of changes in hepatic and peripheral insulin physiology [95].

A low intraluminal pH causes the duodenal mucosa's S cells to produce the 27-amino acid peptide hormone secretin, which suppresses the stomach's parietal cells' ability to secrete gastric acid and promotes the pancreatic centroacinar cells' and intercalated ducts' production of bicarbonate [96,97]. In the duodenum, it emulsifies dietary fats for the action of pancreatic lipase. It also encourages the liver to produce bile. In humans, the secretin gene encodes the secretin peptide [96,97].

A study by Modvig et al. showed that secretin levels were increased following RYGB, indicating that the surgery may enhance secretin secretion through nutrient diversion to the distal small intestine, which could contribute to improved glycemic regulation and metabolic outcomes [98]. One study examined how RYGB affects hormone gene expression and small-intestinal enteroendocrine cell density in individuals with obesity and T2D [99]. Twelve individuals underwent RYGB and were followed by enteroscopy after 10 months. The results showed increased density of cells immunoreactive for GLP-1, CCK, and GIP in post-surgery individuals, while controls showed increases in GLP-1, PYY, CCK, and PC2. Secretin, along with ghrelin and GIP mRNA levels, decreased in both groups post-surgery, while PYY, CCK, NTS, and NR1H4 gene expressions remained unchanged. GCG mRNA increased in both groups. These changes suggest that RYGB induces significant cellular and molecular alterations in enteroendocrine hormones, particularly increasing GLP-1, PYY, CCK, and GIP-producing cell populations, and reducing ghrelin, secretin, and GIP gene expression [99]. Another study assessed the effects of RYGB on enteroendocrine cells in 18 non-diabetic individuals, comparing different biliopancreatic limb lengths [100]. After 12 months, GLP-1 cell density increased nearly fivefold in the jejunum, especially in the BP200 group, with doubled PYY and GIP cell densities. While GLP-1 and PYY mRNA levels decreased, GIP mRNA remained stable. RYGB did not significantly affect the villus length or cell densities of ghrelin, CCK, neurotensin, secretin, or serotonin. The increase in incretin-producing cells likely explains elevated plasma incretin levels post-surgery [100]. Some studies demonstrate that meal-induced secretin activates brown fat thermogenesis, contributing to satiation and increased energy expenditure, highlighting brown adipose tissue's (BAT) potential as a target for obesity treatment [101,102,103]. More research is needed. Interestingly, a recent unknown effect of secretin on activating BAT and on regulating appetite has been reported in humans.

Hormone interactions between the brain and organs of the gastrointestinal tract after MBS are depicted in Figure 2.