Acute Refeeding Research Articles

SCD1 is nutritionally and spatially regulated in the intestine and influences systemic postprandial lipid homeostasis and gut-liver crosstalk

Stearoyl-CoA desaturase-1 is an endoplasmic reticulum (ER)-membrane resident protein that inserts a double bond into saturated fatty acids, converting them into their monounsaturated counterparts. Previous studies have demonstrated an important role for SCD1 in modulating tissue and systemic health. Specifically, lack of hepatic or cutaneous SCD1 results in significant reductions in tissue esterified lipids. While the intestine is an important site of lipid esterification and assimilation into the body, the regulation of intestinal SCD1 or its impact on lipid composition in the intestine and other tissues has not been investigated. Here we report that unlike other lipogenic enzymes, SCD1 is enriched in the distal small intestine and in the colon of chow-fed mice and is robustly upregulated by acute refeeding of a high-sucrose diet. We generated a mouse model lacking SCD1 specifically in the intestine (iKO mice). These mice have significant reductions not only in intestinal lipids, but also in plasma triacylglycerols, diacylglycerols, cholesterol esters, and free cholesterol. Additionally, hepatic accumulation of diacylglycerols is significantly reduced in iKO mice. Comprehensive targeted lipidomic profiling revealed a consistent reduction in the myristoleic (14:1) to myristic (14:0) acid ratios in intestine, liver, and plasma of iKO mice. Consistent with the reduction of the monounsaturated fatty acid myristoleic acid in hepatic lipids of chow fed iKO mice, hepatic expression of Pgc-1α, Sirt1, and related fatty acid oxidation genes were reduced in chow-fed iKO mice. Further, lack of intestinal SCD1 reduced expression of de novo lipogenic genes in distal intestine of chow-fed mice and in the livers of mice fed a lipogenic high-sucrose diet. Taken together, these studies reveal a novel pattern of expression of SCD1 in the intestine. They also demonstrate that intestinal SCD1 modulates lipid content and composition of not only intestinal tissues, but also that of plasma and liver. Further, these data point to intestinal SCD1 as a modulator of gut-liver crosstalk, potentially through the production of novel signaling lipids such as myristoleic acid. These data have important implications to understanding how intestinal SCD1 may modulate risk for post-prandial lipemia, hepatic steatosis, and related pathologies.

Galectin-1 impacts on glucose homeostasis by modulating pancreatic insulin release.

Type-2 diabetes mellitus (T2DM) is an expanding global health problem, involving defective insulin secretion by pancreatic β-cells and peripheral insulin resistance, leading to impaired glucose regulation. Galectin-1-an endogenous lectin with affinity for N-acetyllactosamine (LacNAc)-containing glycans-has emerged as a regulator of inflammatory and metabolic disorders. However, the role of galectin-1 in glucose homeostasis and pancreatic β-cell function, independently of hypercaloric diets, has not been explored. Here, we identified a phenotype compatible with T2DM, involving alterations in glucose metabolism and pancreatic insulin release, in female but not male mice lacking galectin-1 (Lgals1-/-). Compared with age-matched controls, Lgals1-/- female mice exhibited higher body weight and increased food intake ad libitum as well as after fasting and acute re-feeding. Although fasted serum insulin levels and insulin sensitivity were similar in both genotypes, Lgals1-/- female mice presented altered glucose tolerance and higher basal glucose levels depending on the fasting period. Insulin response to glucose overload was impaired, while pancreatic insulin content was enhanced in the absence of galectin-1. Accordingly, recombinant galectin-1 enhanced glucose-stimulated insulin release in vitro. Our study identifies a role for galectin-1 in regulating glucose metabolism through modulation of pancreatic insulin secretion, highlighting novel opportunities to control T2DM.

17β-estradiol promotes acute refeeding in hungry mice via membrane-initiated ERα signaling

ObjectiveEstrogen protects animals from obesity through estrogen receptor α (ERα), partially by inhibiting overeating in animals fed ad libitum. However, the effects of estrogen on feeding behavior in hungry animals remain unclear. In this study, we examined the roles of 17β-estradiol (E2) and ERα in the regulation of feeding in hungry female animals and explored the underlying mechanisms. MethodsWild-type female mice with surgical depletion of endogenous estrogens were used to examine the effects of E2 supplementation on acute refeeding behavior after starvation. ERα-C451A mutant mice deficient in membrane-bound ERα activity and ERα-AF20 mutant mice lacking ERα transcriptional activity were used to further examine mechanisms underlying acute feeding triggered by either fasting or central glucopenia (induced by intracerebroventricular injections of 2-deoxy-D-glucose). We also used electrophysiology to explore the impact of these ERα mutations on the neural activities of ERα neurons in the hypothalamus. ResultsIn the wild-type female mice, ovariectomy reduced fasting-induced refeeding, which was restored by E2 supplementation. The ERα-C451A mutation, but not the ERα-AF20 mutation, attenuated acute feeding induced by either fasting or central glucopenia. The ERα-C451A mutation consistently impaired the neural responses of hypothalamic ERα neurons to hypoglycemia. ConclusionIn addition to previous evidence that estrogen reduces deviations in energy balance by inhibiting eating at a satiated state, our findings demonstrate the unexpected role of E2 that promotes eating in hungry mice, also contributing to the stability of energy homeostasis. This latter effect specifically requires membrane-bound ERα activity.

Increasing lactate levels during treatment of diabetic ketoacidosis

Ayoung woman with type1 diabetes mellitus and severe diabetic ketoacidosis was treated in an intensive care unit according to the guidelines. Only afew hours after starting the therapy, rising lactate values were diagnosed in the arterial blood gas analysis. Since there were no indications for other reasons of lactatemia, an acute refeeding syndrome caused by the insulin therapy was suspected. Thiamine and phosphate were thus replaced. With this treatment, lactate values fell, supporting the hypothesis of lactatemia due to substrate deficiency.

Effects of starvation and short-term refeeding on gastric emptying and postprandial blood glucose regulation in adolescent girls with anorexia nervosa.

Postprandial glucose is reduced in malnourished patients with anorexia nervosa (AN), but the mechanisms and duration for this remain unclear. We examined blood glucose, gastric emptying, and glucoregulatory hormone changes in malnourished patients with AN and during 2 wk of acute refeeding compared with healthy controls (HCs). Twenty-two female adolescents with AN and 17 age-matched female HCs were assessed after a 4-h fast. Patients were commenced on a refeeding protocol of 2,400 kcal/day. Gastric emptying (13C-octanoate breath test), glucose absorption (3-O-methylglucose), blood glucose, plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, C-peptide, and glucagon responses to a mixed-nutrient test meal were measured on admission and 1 and 2 wk after refeeding. HCs were assessed once. On admission, patients had slower gastric emptying, lower postprandial glucose and insulin, and higher glucagon and GLP-1 than HCs ( P < 0.05). In patients with AN, the rise in glucose (0-30 min) correlated with gastric emptying ( P < 0.05). With refeeding, postprandial glucose and 3-O-methylglucose were higher, gastric emptying faster, and baseline insulin and C-peptide less ( P < 0.05), compared with admission. After 2 wk of refeeding, postprandial glucose remained lower, and glucagon and GLP-1 higher, in patients with AN than HCs ( P < 0.05) without differences in gastric emptying, baseline glucagon, or postprandial insulin. Delayed gastric emptying may underlie reduced postprandial glucose in starved patients with AN; however, postprandial glucose and glucoregulatory hormone changes persist after 2 wk of refeeding despite improved gastric emptying. Future research should explore whether reduced postprandial glucose in AN is related to medical risk by examining associated symptoms alongside continuous glucose monitoring during refeeding.

A Case of Possible Acute Refeeding Syndrome: A Review of a Rare, But Potentially Life-Threatening Diagnosis

An 18-year-old Hispanic male presented to the Pediatric Emergency Department with acute on- set of bilateral lower extremity edema. He had no history of similar symptoms. He had recently lost 70 pounds in the past six-months by restricting himself to an extreme diet and exercise regimen. Two days prior to presentation, he resumed a normal diet. In this illustrative case, we describe a case report of possible refeeding syndrome and discuss the presentation, risk factors, management and potential complications of this diagnosis.

Homeostasis alteration within small intestinal mucosa after acute enteral refeeding in total parenteral nutrition mouse model.

Feeding strategies to care for patients who transition from enteral nutrient deprivation while on total parenteral nutrition (TPN) to enteral feedings generally proceed to full enteral nutrition once the gastrointestinal tract recovers; however, an increasing body of literature suggests that a subgroup of patients may actually develop an increased incidence of adverse events, including death. To examine this further, we studied the effects of acute refeeding in a mouse model of TPN. Interestingly, refeeding led to some beneficial effects, including prevention in the decline in intestinal epithelial cell (IEC) proliferation. However, refeeding led to a significant increase in mucosal expression of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), as well as an upregulation in Toll-like receptor 4 (TLR-4). Refeeding also failed to prevent TPN-associated increases in IEC apoptosis, loss of epithelial barrier function, and failure of the leucine-rich repeat-containing G protein-coupled receptor 5-positive stem cell expression. Transitioning from TPN to enteral feedings led to a partial restoration of the small bowel microbial population. In conclusion, while acute refeeding led to some restoration of normal gastrointestinal physiology, enteral refeeding led to a significant increase in mucosal inflammatory markers and may suggest alternative strategies to enteral refeeding should be considered.

Circulating FGF21 Is Liver Derived and Enhances Glucose Uptake During Refeeding and Overfeeding

Fibroblast growth factor (FGF)21 is an endocrine hormone that is expressed in multiple tissues and functions physiologically to maintain energy homeostasis. FGF21 is being pursued as a therapeutic target for diabetes and obesity because of its rapid and potent effects on improving insulin sensitivity. However, whether FGF21 enhances insulin sensitivity under physiologic conditions remains unclear. Here, we show that liver-derived FGF21 enters the circulation during fasting but also remains present and functional during the early stage of refeeding. After a prolonged fast, FGF21 acts as an insulin sensitizer to overcome the peripheral insulin resistance induced by fasting, thereby maximizing glucose uptake. Likewise, FGF21 is produced from the liver during overfeeding and mitigates peripheral insulin resistance. DIO FGF21 liver-specific knockout, but not FGF21 adipose-specific knockout, mice have increased insulin resistance and decreased brown adipose tissue–mediated glucose disposal. These data are compatible with the concept that FGF21 functions physiologically as an insulin sensitizer under conditions of acute refeeding and overfeeding.

Guideline Watch (August 2012): Practice Guideline for the Treatment of Patients With Eating Disorders, 3rd Edition

This guideline watch reviews new evidence and highlights salient developments since the 2006 publication of APA’s Practice Guideline for the Treatment of Patients With Eating Disorders, 3rd Edition. The authors of this watch constituted the work group that developed the 2006 guideline. We find the guideline to remain substantially correct and current in its recommendations. The sole exception is a recommendation (with moderate-level confidence) for sibutramine for binge-eating disorder. In 2010, the U.S. Food and Drug Administration (FDA) withdrew approval for sibutramine because clinical trials showed increased risk of heart attack and stroke, and the manufacturer, Abbott Laboratories, subsequently withdrew this medication from the U.S. market. Noteworthy recent publications about the treatment of eating disorders include systematic reviews by the Agency for Healthcare Research and Quality (Berkman et al. 2006; Bulik et al. 2007); practice guidelines from international groups, including the Catalan Agency for Health Information, Assessment and Quality (Working Group of the Clinical Practice Guideline for Eating Disorders 2009), the World Federation of Societies of Biological Psychiatry (Aigner et al. 2011), and the German Society of Psychosomatic Medicine and Psychotherapy and the German College for Psychosomatic Medicine (Herpertz et al. 2011); and a 2011 guidance statement by the Academy for Eating Disorders, which was written by some of the authors of this

Deferred feeding and body weight responses to short-term interruption of fuel acquisition: impact of estradiol.

Short-term abstinence from food intake, planned or unplanned, is unavoidable in modern life, but negatively correlated with appetite control and obesity. This study investigated the role of estradiol in feeding and body weight (BW) reactions to short-span cessation of feeding. During acute 1-6-h re-feeding, 12-h food-deprived (FD), estradiol benzoate (EB)-implanted ovariectomized rats ate less food and gained less weight than FD animals implanted with oil (O). Full fed (FF)- and FD-EB consumed equal amounts of food over 24 h, but weight gain was greater in the latter; 24-h food intake and BW gain in FD-O exceeded FD-EB. Caudal fourth ventricular administration of the AMPK activator AICAR increased dorsal vagal complex AMPK activity in FD-EB and FD-O, but elicited dissimilar adjustments in hypothalamic metabolic neuropeptide transmitter expression, while respectively enhancing or reducing acute re-feeding in these animals and reversing FD-O weight gain. Drug-treated FD-EB and FD-O exhibited respective feeding and weight gain increases between 6-24 h. AICAR enhanced 24-h consumption in FD-EB vs. FF-EB, but cumulative intake and BW gain were greater in AICAR-treated FD-O vs. FD-EB. Results show that estradiol limits acute re-feeding after short-term feeding suspension, but augments acute re-feeding when energy depletion coincides with suspended feeding. This compound metabolic stress exerts steroid-dependent effects during later resumption of circadian-induced feeding, for example, increased consumption vs. weight gain in the presence vs. absence of estradiol. These studies provide novel evidence that estrogen mitigates acute and post-acute adverse effects of disrupted fuel acquisition on energy balance.

The Temporal Pattern of cfos Activation in Hypothalamic, Cortical, and Brainstem Nuclei in Response to Fasting and Refeeding in Male Mice

In this study we examined fasted and refed cfos activation in cortical, brainstem, and hypothalamic brain regions associated with appetite regulation. We examined a number of time points during refeeding to gain insight into the temporal pattern of neuronal activation and changes in endocrine parameters associated with fasting and refeeding. In response to refeeding, blood glucose and plasma insulin returned to basal levels within 30 minutes, whereas plasma nonesterified fatty acids and leptin returned to basal levels after 1 and 2 hours, respectively. Within the hypothalamic arcuate nucleus (ARC), fasting increased cfos activation in ∼25% of neuropeptide Y neurons, which was terminated 1 hour after refeeding. Fasting had no effect on cfos activation in pro-opiomelanocortin neurons; however, 1 and 2 hours of refeeding significantly activated ∼20% of ARC pro-opiomelanocortin neurons. Acute refeeding (30, 60, and 120 minutes), but not fasting, increased cfos activation in the nucleus accumbens, the cingulate cortex (but not the insular cortex), the medial and lateral parabrachial nucleus, the nucleus of the solitary tract, the area postrema, the dorsal raphe, and the ventromedial nucleus of the hypothalamus. After 6 hours of refeeding, cfos activity was reduced in the majority of these regions compared with that at earlier time points. Our data indicate that acute refeeding, rather than long-term fasting, activates cortical, brainstem, and hypothalamic neural circuits associated with appetite regulation and reward processing. Although the hypothalamic ARC remains a critical sensory node detecting changes in the metabolic state and feedback during fasting and acute refeeding, our results also reveal the temporal pattern in cfos activation in cortical and brainstem areas implicated in the control of appetite and body weight regulation.

Hypolipidemic action of the SERM acolbifene is associated with decreased liver MTP and increased SR-BI and LDL receptors

This study aimed to identify the mechanisms of the hypolipidemic action of the selective estrogen receptor modulator (SERM) acolbifene (ACOL). Four weeks of treatment with ACOL reduced fasting and postprandial plasma triglycerides (TGs), an effect associated with lower VLDL-TG secretion rate (-25%), and decreased mRNA of microsomal triglyceride transfer protein (MTP; -29%). ACOL increased liver TG concentration (+100%) and amplified the feeding-induced increase in the master lipogenic regulators sterol-regulatory element binding protein-1a (SREBP-1a) and SREBP-1c. ACOL decreased total, HDL, and non-HDL cholesterol (CHOL) by 50%. SREBP-2 mRNA and HMG-CoA reductase activity were minimally affected by ACOL. However, in the fasted state, liver concentration of scavenger receptor class B type I (SR-BI) protein, but not mRNA, was 3-fold higher in ACOL-treated than in control animals and correlated with plasma HDL-CHOL levels (r = 0.80, P < 0.002). Liver LDL receptor (LDLR) protein, but not mRNA, was increased 2-fold by ACOL, independently of the nutritional status. This study demonstrates that ACOL possesses the unique ability among SERMs to reduce VLDL-TG secretion, likely by reducing MTP expression, and strongly suggests that the robust hypocholesterolemic action of ACOL is related to increased removal of CHOL from the circulation as a consequence of enhanced liver SR-BI and LDLR abundance.

Acute Re-Feeding Reverses Food Restriction-Induced Hypothalamic-Pituitary-Gonadal Axis Deficits1

Undernutrition has well-established effects on female reproduction. Here we describe the effects of food restriction on aspects of the hypothalamic-pituitary-gonadal (HPG) axis in the female musk shrew. We determined that acute re-feeding reverses deficits brought on by food restriction. Two days of food restriction led to an increase in proGnRH immunoreactive cells in the preoptic area relative to ad libitum-fed controls (AL). This increase was reversed by 90 min of ad libitum feeding in the re-fed females (RF). In addition, food-restricted (FR) females had significantly greater GnRH content in the median eminence than either the AL or RF females. After GnRH was administered, the majority of females in all food conditions ovulated, yet the FR females had significantly fewer corpora lutea than either the AL or RF animals. These data show that food restriction impairs HPG axis function in female musk shrews, and that some of these impairments can be rapidly reversed by acute re-feeding.

Resting energy expenditure and plasma leptin levels in anorexia nervosa during acute refeeding

To examine changes in plasma leptin levels and resting energy expenditure (REE) during short-term refeeding of patients with anorexia nervosa (AN). This was a longitudinal study of 21 women meeting the DSM-IV criteria for AN who were admitted to the hospital for renutrition. Height, weight, percent body fat (assessed by skin fold thickness), REE (measured by indirect calorimetry), and circulating plasma leptin concentration were assessed at the time of admission and 7 days later. Over the course of 1 week of refeeding, body mass index (BMI) increased 0.75 +/- 0.15 kg/m(2) (p <.0001), body fat increased 0.9 +/- 0.2% (p <.0001), and REE increased 107 +/- 33 kcal/24 hr (p =.0037). The change in mean leptin levels was not statistically significant (0.45 +/- 0.44 ng/ml; p =.32). Leptin is unlikely responsible for the increase in REE observed with short-term refeeding.

Effects of protein restriction and acute refeeding on leucine and lysine kinetics in young men.

To explore the effects of altered protein intake on the uptake and utilization of dietary amino acids in human subjects, six healthy male Massachusetts Institute of Technology students were studied during three dietary periods each of 9 days, with tracer infusion studies conducted on days 8 and 9. During one period the diet provided a generous protein intake (1.5 g.kg-1.day-1) and during the other two a low-protein intake (0.1 g.kg-1.day-1). Tracer infusions (fed state) were given while subjects received either a liquid formula, supplying the prior protein intake or (on day 9) a generous intake. Combinations of [2H3]Leu and [13C]Leu and of [15N]Lys and [2H4]Lys were given via continuous intravenous or intragastric infusion for 4 h to estimate leucine kinetics and the first-pass splanchnic uptake of tracer. Dietary-induced changes in leucine flux and oxidation were similar irrespective of the tracer and/or route of administration and sampled pool (leucine or KIC) used for calculation. Estimates of absolute changes in the rates of leucine disappearance via nonoxidative metabolism (protein synthesis) and of appearance via protein breakdown depended on the route of [13C]Leu administration. However, it appears that both altered rates of protein synthesis and breakdown contribute to the adaptations required in the body nitrogen economy when protein intakes are restricted and subsequently resupplied. From the intragastric [13C]Leu protocol, the first-pass splanchnic uptake of tracer was the same (approximately 30%) for generous, low-protein, and refed conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of acute fasting and refeeding on glucose utilization in healthy women.

Influence of acute fasting and refeeding on glucose utilization in healthy women.