Hypothalamic control of body fat mass by food intake: The key to understanding why obesity should be treated as a disease.

BACKGROUND: Hypothalamic centres have been recognized to play a central role in body weight regulation for nearly 70 years. AIMS: In this review, we will explore the current undersanding of the role the hypothalamus plays in controlling food intake behaviours. MATERIALS AND METHODS: Review of relevant literature from PubMed searches and review article citations. RESULTS: Beginning with autopsy studies showing destructive hypothalamic lesions in patients manifesting hyperphagia and rapid weight gain, followed by animal lesioning studies pinpointing adjacent hypothalamic sites as the 'satiety' centre and the 'feeding' centre of the brain, the neurocircuitry that governs our body weight is now understood to consist of a complex, interconnected network, including the hypothalamus and extending to cortical sites, reward centres and brainstem. Neurons in these sites receive afferent signals from the gastrointestinal tract and adipose tissue indicating food availability, calorie content, as well as body fat mass. DISCUSSION: Integration of these complex signals leads to modulation of the two prime effector systems that defend a body fat mass set point: food intake and energy expenditure. CONCLUSION: Understanding the hypothalamic control of food intake forms the foundation for understanding and managing obesity as a chronic disease.

"I am terrified of something happening to me" The lived experience of people with obesity during the COVID-19 pandemic.

Obesity is emerging as a risk factor for COVID-19 disease severity. The impact of the pandemic and knowledge of obesity as a risk factor on the lived experience of people with obesity is not fully understood. The aim of this study was to investigate the impact of the COVID-19 pandemic on people living with severe obesity (BMI ≥35 kg/m2 ), currently engaged in multi-modal treatment. The primary objectives were to examine the impact of the pandemic on their lived experience from a treatment and psychosocial standpoint and additionally explore their awareness of obesity as a risk factor for COVID-19 disease severity. An in-depth qualitative study was adopted employing semi-structured interviews with open-ended questions. Interpretive thematic analysis was adopted to analyse the data and identify key themes taking a grounded approach. Themes that emerged from the perspective of impact on lived experience were (a) challenge sustaining treatment and (b) psychosocial impact. There was an even split regarding awareness and lack of awareness of obesity as risk factor which itself contributes towards a negative psychosocial impact in most patients. The COVID-19 pandemic is posing a diverse challenge to people with obesity. This has implications for their on-going treatment. From an ethical standpoint, there is a need to fully elucidate the link between obesity and COVID-19, disseminate this information using people friendly language and imagery in a manner that does not exacerbate a harmful psychosocial response or lead to stigmatization.

Suppression of enteroendocrine cell glucagon-like peptide (GLP)-1 release by fat-induced small intestinal ketogenesis: a mechanism targeted by Roux-en-Y gastric bypass surgery but not by preoperative very-low-calorie diet.

OBJECTIVE: Food intake normally stimulates release of satiety and insulin-stimulating intestinal hormones, such as glucagon-like peptide (GLP)-1. This response is blunted in obese insulin resistant subjects, but is rapidly restored following Roux-en-Y gastric bypass (RYGB) surgery. We hypothesised this to be a result of the metabolic changes taking place in the small intestinal mucosa following the anatomical rearrangement after RYGB surgery, and aimed at identifying such mechanisms. DESIGN: Jejunal mucosa biopsies from patients undergoing RYGB surgery were retrieved before and after very-low calorie diet, at time of surgery and 6 months postoperatively. Samples were analysed by global protein expression analysis and Western blotting. Biological functionality of these findings was explored in mice and enteroendocrine cells (EECs) primary mouse jejunal cell cultures. RESULTS: The most prominent change found after RYGB was decreased jejunal expression of the rate-limiting ketogenic enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHMGCS), corroborated by decreased ketone body levels. In mice, prolonged high-fat feeding induced the expression of mHMGCS and functional ketogenesis in jejunum. The effect of ketone bodies on gut peptide secretion in EECs showed a ∼40% inhibition of GLP-1 release compared with baseline. CONCLUSION: Intestinal ketogenesis is induced by high-fat diet and inhibited by RYGB surgery. In cell culture, ketone bodies inhibited GLP-1 release from EECs. Thus, we suggest that this may be a mechanism by which RYGB can remove the inhibitory effect of ketone bodies on EECs, thereby restituting the responsiveness of EECs resulting in increased meal-stimulated levels of GLP-1 after surgery.

Iron and Vitamin D/Calcium Deficiency after Gastric Bypass: Mechanisms Involved and Strategies to Improve Oral Supplement Disposition.

BACKGROUND: Nutritional deficiencies are common following Roux-en-Y Gastric Bypass (RYGB). Aetiology is diverse; including non-compliance, altered diet, unresolved preoperative deficiency and differential degrees of post-operative malabsorption occurring as function of length of bypassed intestine. Iron and calcium/vitamin D deficiency occur in up to 50% of patients following RYGB. Currently, treatment strategies recommend the prescription of oral supplements for those who become deficient. Meanwhile, debate exists regarding the absorption capacity of these post-operatively and their efficacy in treating deficiency. OBJECTIVE: To examine the disposition of oral iron and calcium/vitamin D supplementation following RYGB. METHODS: A literature review was carried out using PubMed and Embase. Data from the key interventional studies investigating iron and calcium/vitamin D oral supplement absorption and efficacy following RYGB was summarized. RESULTS: Absorption of both iron and vitamin D/calcium is adversely affected following RYGB. Distribution and metabolism may be altered by the predominance of paracellular absorption pathways which promote unregulated influx into the circulatory system. Overall, studies indicate that current supplementation strategies are efficacious to a degree in treating deficiency following RYGB, generally restoration of optimal status is not achieved. CONCLUSION: Oral supplement disposition is altered following RYGB. As a result, patients are required to take regimens of oral supplementation indefinitely. The dosage which confers optimum health benefit while avoiding potential toxicity and tolerability issues remains unknown. Novel preparations with improved disposition could help limit the extent of post-RYGB nutritional deficiencies.

Optimisation of follow-up after metabolic surgery.

Bariatric surgery has many benefits beyond weight loss, including improved control of glycaemia, blood pressure, and dyslipidaemia; hence, such surgery has been rebranded as metabolic surgery. The operations are, unfortunately, also associated with major surgical and medical complications. The medical complications include gastro-oesophageal reflux disease, malnutrition, and metabolic complications deriving from vitamin and mineral malabsorption. The benefits of surgery can be optimised by implementing specific protocols before and after surgery. In this Review, we discuss the assessment of the risk of major cardiac complications and severe obstructive sleep apnoea before surgery, and the provision of adequate lifelong postsurgery nutritional, vitamin, and mineral supplementation to reduce complications. Additionally, we examine the best antidiabetic medications to reduce the risk of hypoglycaemia after gastric bypass and sleeve gastrectomy, and the strategies to improve weight loss or reduce weight regain. Although optimising clinical pathways is possible to maximise metabolic benefits and reduce the risks of complications and micronutrient deficiencies, evolution of these strategies can further improve the risk-to-benefit ratio of metabolic surgery.

Elevated fasting and postprandial C-terminal telopeptide after Roux-en-Y gastric bypass.

Background Roux-en-Y gastric bypass increases circulating bile acid concentrations, known mediators of postprandial suppression of markers of bone resorption. Long-term data, however, indicate that Roux-en-Y gastric bypass confers an increased risk of bone loss on recipients. Methods Thirty-six obese individuals, median age 44 (26-64) with median body mass index at baseline of 42.5 (40.4-46) were studied before and 15 months after Roux-en-Y gastric bypass. After an overnight fast, patients received a 400 kcal mixed meal. Blood samples were collected premeal then at 30-min periods for 120 min. Pre and postmeal samples were analysed for total bile acids, parathyroid hormone and C-terminal telopeptide. Results Body weight loss post Roux-en-Y gastric bypass was associated with a median 4.9-fold increase in peak postprandial total bile acid concentration, and a median 2.4-fold increase in cumulative food evoked bile acid response. Median fasting parathyroid hormone, postprandial reduction in parathyroid hormone and total parathyroid hormone release over 120 min remained unchanged after surgery. After surgery, median fasting C-terminal telopeptide increased 2.3-fold, peak postprandial concentrations increased 3.8-fold and total release was increased 1.9-fold. Conclusions Fasting and postprandial total bile acids and C-terminal telopeptide are increased above reference range after Roux-en-Y gastric bypass. These changes occur in spite of improved vitamin D status with supplementation. These results suggest that post-Roux-en-Y gastric bypass increases in total bile acids do not effectively oppose an ongoing resorptive signal operative along the gut-bone axis. Serial measurement of C-terminal telopeptide may be of value as a risk marker for long-term skeletal pathology in patients post Roux-en-Y gastric bypass.

Differences in Regional Brain Responses to Food Ingestion After Roux-en-Y Gastric Bypass and the Role of Gut Peptides: A Neuroimaging Study.

OBJECTIVE: Improved appetite control, possibly mediated by exaggerated gut peptide responses to eating, may contribute to weight loss after Roux-en-Y gastric bypass (RYGB). This study compared brain responses to food ingestion between post-RYGB (RYGB), normal weight (NW), and obese (Ob) unoperated subjects and explored the role of gut peptide responses in RYGB. RESEARCH DESIGN AND METHODS: Neuroimaging with [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography was performed in 12 NW, 21 Ob, and 9 RYGB (18 ± 13 months postsurgery) subjects after an overnight fast, once FED (400 kcal mixed meal), and once FASTED, in random order. RYGB subjects repeated the studies with somatostatin infusion and basal insulin replacement. Fullness, sickness, and postscan ad libitum meal consumption were measured. Regional brain FDG uptake was compared using statistical parametric mapping. RESULTS: RYGB subjects had higher overall fullness and food-induced sickness and lower ad libitum consumption. Brain responses to eating differed in the hypothalamus and pituitary (exaggerated activation in RYGB), left medial orbital cortex (OC) (activation in RYGB, deactivation in NW), right dorsolateral frontal cortex (deactivation in RYGB and NW, absent in Ob), and regions mapping to the default mode network (exaggerated deactivation in RYGB). Somatostatin in RYGB reduced postprandial gut peptide responses, sickness, and medial OC activation. CONCLUSIONS: RYGB induces weight loss by augmenting normal brain responses to eating in energy balance regions, restoring lost inhibitory control, and altering hedonic responses. Altered postprandial gut peptide responses primarily mediate changes in food-induced sickness and OC responses, likely to associate with food avoidance.

Capsaicin-induced satiety is associated with gastrointestinal distress but not with the release of satiety hormones.

BACKGROUND: Capsaicin, which is the major pungent principle in chili peppers, is able to induce satiety and reduce caloric intake. The exact mechanism behind this satiating effect is still unknown. We hypothesized that capsaicin induces satiety through the release of gastrointestinal peptides, such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), from enteroendocrine cells in the small intestine. OBJECTIVE: We investigate the effects of an intraduodenal capsaicin infusion (1.5 mg pure capsaicin) in healthy volunteers on hunger, satiety, and gastrointestinal symptoms and the release of GLP-1 and PYY. DESIGN: Thirteen participants (7 women) [mean ± SEM age: 21.5 ± 0.6 y; body mass index (in kg/m(2)): 22.8 ± 0.6] participated in this single-blind, randomized, placebo-controlled crossover study with 2 different treatments. During test days, an intraduodenal infusion of either capsaicin or a placebo (physiologic saline) was performed with the use of a nasoduodenal catheter over a period of 30 min. Visual analog scale scores were used to measure hunger, satiety, and gastrointestinal symptoms. Blood samples were drawn at regular intervals for GLP-1 and PYY. Gallbladder volumes were measured with the use of real-time ultrasonography. RESULTS: The intraduodenal capsaicin infusion significantly increased satiety (P-treatment effect < 0.05) but also resulted in an increase in the gastrointestinal symptoms pain (P-treatment × time interaction < 0.0005), burning sensation (P-treatment × time interaction < 0.0001), nausea (P-treatment × time interaction < 0.05), and bloating (P-treatment × time interaction < 0.001) compared with the effects of the placebo infusion. Satiety scores had a positive correlation with all gastrointestinal symptoms. No differences in GLP-1 and PYY concentrations and gallbladder volumes were observed after the capsaicin infusion compared with after the placebo infusion. CONCLUSIONS: An intraduodenal infusion of capsaicin significantly increases satiety but does not affect plasma concentrations of GLP-1 and PYY. Rather, the effect on satiety seems related to gastrointestinal stress as shown by the associations with pain, burning sensation, nausea, and bloating scores. This trial was registered at clinicaltrials.gov as NCT01667523.

Reduced sweet and fatty fluid intake after Roux-en-Y gastric bypass in rats is dependent on experience without change in stimulus motivational potency.

Here we assessed how intake reductions induced by Roux-en-Y gastric bypass surgery (RYGB) occur within and across access periods by examining drinking microstructure. After training, RYGB (n = 8-10) or sham-operated (SHAM, n = 12) rats were given 60-min access first to 0.3 M sucrose, then to 5% Intralipid, and finally to milk-chocolate Ensure Plus across 5 days each. Initially, total licks taken during the first meal of sucrose and Intralipid by RYGB and SHAM rats did not differ, but, across subsequent test periods, RYGB rats licked less than SHAM rats. First Ensure meal size also did not differ between RYGB and SHAM rats, but SHAM rats increased licking across test periods while the behavior of RYGB rats remained stable. The intake differences between the surgical groups, when they occurred, were most often due to smaller burst sizes in RYGB rats. Importantly, the surgical-group difference in sucrose and Intralipid intakes could not be explained by altered palatability of these solutions because, throughout testing, both groups had similar early meal licking behavior thought to represent the motivational potency of stimulus orosensory features. Although, overall, RYGB rats displayed lower early meal licking of Ensure relative to the SHAM rats, this appeared to be driven primarily by increases in the latter group across test periods; the RYGB group stayed relatively stable. Collectively, these results suggest that some level of postoral experience with these stimuli and/or their components is necessary before intake differences emerge between surgical groups, and, even when differences occur, often immediate taste-motivated ingestive behavior remains unaltered.

Gastric bypass in rats does not decrease appetitive behavior towards sweet or fatty fluids despite blunting preferential intake of sugar and fat.

After Roux-en-Y gastric bypass (RYGB) surgery, patients report consuming fewer fatty and dessert-like foods, and rats display blunted sugar and fat preferences. Here we used a progressive ratio (PR) task in our rat model to explicitly test whether RYGB decreases the willingness of rats to work for very small amounts of preferred sugar- and/or fat-containing fluids. In each of two studies, two groups of rats - one maintained on a high-fat diet (HFD) and standard chow (CHOW) and one given CHOW alone - were trained while water-deprived to work for water or either Ensure or 1.0M sucrose on increasingly difficult operant schedules. When tested before surgery while nondeprived, HFD rats had lower PR breakpoints (number of operant responses in the last reinforced ratio) for sucrose, but not for Ensure, than CHOW rats. After surgery, at no time did rats given RYGB show lower breakpoints than SHAM rats for Ensure, sucrose, or when 5% Intralipid served postoperatively as the reinforcer. Nevertheless, RYGB rats showed blunted preferences for these caloric fluids versus water in 2-bottle preference tests. Importantly, although the Intralipid and sucrose preferences of RYGB rats decreased further over time, subsequent breakpoints for them were not significantly impacted. Collectively, these data suggest that the observed lower preferences for normally palatable fluids after RYGB in rats may reflect a learned adjustment to altered postingestive feedback rather than a dampening of the reinforcing taste characteristics of such stimuli as measured by the PR task in which postingestive stimulation is negligible.

Copper, selenium and zinc levels after bariatric surgery in patients recommended to take multivitamin-mineral supplementation.

BACKGROUND: Bariatric surgery is widely performed to improve obesity-related disorders, but can lead to nutrient deficiencies. In this study we examined serum trace element concentrations before and after bariatric surgery. METHODS: We obtained serum trace element concentrations by inductively coupled plasma-mass spectrometry (ICP-MS) method in 437 patients (82% women, median preoperative body-mass index 46.7 kg/m(2) [interquartile range 42-51]) undergoing either gastric banding (22.7%), sleeve gastrectomy (20.1%), or gastric bypass (57.3%) procedures. Trace element data were available for patients preoperatively (n = 44); and 3 (n = 208), 6 (n = 174), 12 (n = 122), 18 (n = 39), 24 (n = 44) and 36 months (n = 14) post-operatively. All patients were recommended to take a multivitamin-mineral supplement after surgery. RESULTS: Copper deficiency was found in 2% of patients before surgery; and after surgery deficiency rates ranged from 0 to 5% with no significant change in median concentrations during follow-up (p = 0.68). Selenium deficiency was reported in 2% of patients before surgery; and after surgery deficiency rates ranged from 11 to 15% with a near-significant change in median concentrations (p = 0.056). Zinc deficiency was reported in 7% before surgery; and after surgery deficiency rates ranged from 7 to 15% with no significant change in median concentrations (p = 0.39). CONCLUSIONS: In bariatric surgery patients recommended to take multivitamin-mineral supplements, serum copper, zinc and selenium concentrations were mostly stable during the first years after bariatric surgery. There was a possible tendency for selenium concentrations to decline during the early postoperative period.

Adherence to the National Institute of Clinical Excellence guidance on parenteral nutrition screening is not enough to improve outcomes.

BACKGROUND & AIM: Majority of the National Institute of Clinical Excellence (NICE) nutrition guidance recommendations were based on Grade D evidence due to absence of randomised controlled trials. The aim was to assess outcomes of parenteral nutrition (PN) administration when the guidance was adhered to. METHODS: The prospective study included patients referred for PN. Patients were divided into two groups: guidance compliant and guidance non-compliant. Primary outcome measures were duration of PN treatment, number of PN bags used per patient, length of hospital stay and mortality. RESULTS: There were 262 patients, aged 54(42-67) [median (IQR)] years. The guidance compliant and the non-compliant groups consisted of 143 and 119 patients respectively. In the guidance compliant group all patients were screened on admission compared to 40% in the non-compliant group (p < 0.001). Among those malnourished/at risk of malnutrition all were referred for early dietetic assessment in the compliant group but only 14% in the non-compliant group (p < 0.001). There was no difference in any of the outcome measures between the groups. CONCLUSION: Compliance with the nutritional guidance in the UK was not enough to improve outcomes in patients requiring PN in our cohort. Evidence based changes to PN practice are required to optimise care.

Serum total cortisol and free cortisol index give different information regarding the hypothalamus-pituitary-adrenal axis reserve in patients with liver impairment.

BACKGROUND: The short synacthen test (SST) is used to investigate patients with suspected hypothalamus-pituitary-adrenal (HPA) axis pathology. A rise of serum total cortisol (total cortisol) above 550 nmol/L is accepted as sufficient adrenal reserve. In total, 80% of cortisol is bound to cortisol-binding globulin (CBG) and 10% to albumin. In the acute phase responses CBG concentrations decrease and can influence the interpretation of SST. The free cortisol index (FCI) is a surrogate marker for free cortisol and is defined as total cortisol (nmol/L)/CBG (mg/L) with an FCI > 12 representing sufficient adrenal reserve. The aim of this study was to compare total cortisol and FCI in the interpretation of SST in patients with liver impairment. METHOD: SST was done on 26 patients with liver impairment. Total cortisol was measured on Advia Centaur; serum CBG by radioimmunoassay and FCI calculated. RESULTS: Eleven (42%) patients had a total cortisol >550 nmol/L (range 555-2070) and FCI > 12 (12.0-68.9) suggesting sufficient cortisol reserve. Three patients (13%) had total cortisol <550 nmol/L (268-413) and FCI < 12 (3.5-11.6) consistent with cortisol deficiency. Twelve patients (46%) had a total cortisol <550 nmol/L (144-529), but an FCI > 12 (12.0-52.9). None of the patients had a total cortisol >550 nmol/L and FCI < 12. CONCLUSION: When total cortisol alone is used to interpret SST in patients with liver impairment, 46% may have been classified as having adrenal insufficiency because of low CBG. FCI may be better for the evaluation of HPA axis insufficiency in patients with liver impairment.

After bariatric surgery, what vitamins should be measured and what supplements should be given?

Bariatric surgery is the most effective treatment for morbid obesity. Although calorie malabsorption does not occur in most bariatric procedures, micronutrient deficiencies are possible. Multivitamin supplementation is essential following bariatric surgery. The recommendation would be to screen for multivitamin deficiencies prior to surgery and to monitor vitamin levels postoperatively at regular intervals. In this paper, we review the data for screening and supplementation after bariatric procedures for different vitamins.

Mechanisms of weight loss after gastric bypass and gastric banding.

The obesity epidemic is a major health problem that is associated with increased morbidity and mortality. Gastrointestinal hormones have been increasingly understood to be an important element in appetite regulation. Several gastrointestinal hormones can contribute to obesity by modulating the activity of the gut-brain axis. Bariatric surgery is currently the most effective therapy for significant and sustained weight loss in morbidly obese patients. Understanding how gut hormones are altered by bariatric procedures has contributed to our understanding of the mechanisms of appetite. In this review, we address several gastrointestinal hormones that are associated with obesity and consider how their levels are altered after bariatric surgery. The review also addresses specific effects of different gut hormones on appetite, hunger, and energy balance.

The effect of Khat (Catha edulis) as an appetite suppressant is independent of ghrelin and PYY secretion.

BACKGROUND: The leaves of the khat plant (Catha edulis) are chewed for their pleasurable effects. Chewing releases cathinone which may decrease appetite through an unknown mechanism. Levels of the peptide ghrelin increase with hunger and decrease immediately post-prandially, while peptide YY is released following a meal. We hypothesised that the anorexigenic effects of khat may be mediated through changes in these hormones. MATERIALS AND METHODS: Six habitual khat chewers attended on two separate occasions. For a period of 3h they chewed either khat leaves or lettuce. Blood pressure (BP) and pulse rate (PR) were monitored throughout, as were subjective assessments of hunger and fullness. Plasma samples were analysed for cathinone, ghrelin and PYY levels. RESULTS: Chewing khat significantly decreased subjective feelings of hunger and increased fullness (p<0.05) but had no effect on ghrelin and PYY levels. Khat led to an increase in cathinone levels as well as an increase in BP and PR. Cathinone levels correlated positively with fullness and pulse rate and negatively with hunger. CONCLUSIONS: Chewing khat decreases subjective feelings of hunger and increases systemic sympathetic tone, but has no effect on ghrelin and PYY levels. We conclude that the anorexigenic effect of khat may be secondary to central mechanisms mediated via cathinone.