Sex Differences in Liver, Adipose Tissue, and Muscle Transcriptional Response to Fasting and Refeeding in Mice.

Fasting is often used for obesity correction but the "refeeding syndrome" limits its efficiency, and molecular mechanisms underlying metabolic response to different food availability are under investigation. Sex was shown to affect hormonal and metabolic reactions to fasting/refeeding. The aim of this study was to evaluate hormonal and transcriptional responses to fasting and refeeding in male and female C57Bl/6J mice. Sex asymmetry was observed both at the hormonal and transcriptional levels. Fasting (24 h) induced increase in hepatic Fgf21 gene expression, which was associated with elevation of plasma FGF21 and adiponectin levels, and the upregulation of expression of hepatic (Pparα, Cpt1α) and muscle (Cpt1ß, Ucp3) genes involved in fatty acid oxidation. These changes were more pronounced in females. Refeeding (6 h) evoked hyperinsulinemia and increased hepatic expression of gene related to lipogenesis (Fasn) only in males and hyperleptinemia and increase in Fgf21 gene expression in muscles and adipose tissues only in females. The results suggest that in mice, one of the molecular mechanisms underlying sex asymmetry in hepatic Pparα, Cpt1α, muscle Cpt1ß, and Ucp3 expression during fasting is hepatic Fgf21 expression, and the reason for sex asymmetry in hepatic Fasn expression during refeeding is male-specific hyperinsulinemia.

Increased risk of refeeding syndrome-like hypophosphatemia with high initial amino acid intake in small-for-gestational-age, extremely-low-birthweight infants.

BACKGROUND: Recent nutrition guidelines for extremely-low-birth-weight infants (ELBWIs) recommend implementation of high initial amino acid (AA) supplementation in parenteral nutrition. OBJECTIVE: We sought to evaluate the influence of AA intake on refeeding syndrome-like electrolyte disturbances including hypophosphatemia in ELBWIs. STUDY DESIGN: Medical records of 142 ELBWIs were reviewed. Demographic, nutritional, outcome, and electrolyte data were compared between ELBWIs with initial low (1.5 g/kg/day) and high (3 g/kg/day) AA intake. Multivariate analysis was conducted to determine the odds ratio of hypophosphatemia with high AA intake and small-for-gestational-age (SGA) ELBWIs. RESULTS: The incidence of hypophosphatemia and severe hypophosphatemia increased from 51% and 8% in period I to 59% and 20% in period II, respectively (p = 0.36 and < 0.01). Specifically, SGA ELBWIs showed higher incidence of hypophosphatemia than appropriate-for-gestational age (AGA) ELBWIs in period II, whereas there was no difference in period I. For severe hypophosphatemia, SGA ELBWIs presented a 27% incidence versus a 2% incidence in AGA ELBWIs, even with low initial AA intake. Despite no difference in phosphate intake between infants with and without hypophosphatemia, serum phosphate level reached a nadir at the sixth postnatal day and gradually recovered over the second week in infants with hypophosphatemia. In multivariate analyses, the odds ratios for severe hypophosphatemia were 3.6 and 6.6 with high AA intake and SGA status, respectively, with the highest being 18.0 with combined high AA intake and SGA status. CONCLUSIONS: In summary, high initial AA intake significantly increased the risk of refeeding syndrome-like electrolyte dysregulations including severe hypophosphatemia in ELBWIs. In SGA ELBWIs, the risk of electrolyte disturbance was significantly higher, even with low initial AA intake. Therefore, new tailored parenteral nutrition protocols starting with lower energy intake and a gradual increase over the first week may be warranted for application in high-risk SGA ELBWIs.

The refeeding syndrome. Importance of phosphorus. / El síndrome de realimentación. Importancia del fósforo.

Refeeding syndrome (RS) is a complex disease that occurs when nutritional support is initiated after a period of starvation. The hallmark feature is the hypophosphataemia, however other biochemical abnormalities like hypokalaemia, hypomagnesaemia, thiamine deficiency and disorder of sodium and fluid balance are common. The incidence of RS is unknown as no universally accepted definition exists, but it is frequently underdiagnosed. RS is a potentially fatal, but preventable, disorder. The identification of patients at risk is crucial to improve their management. If RS is diagnosed, there is one guideline (NICE 2006) in place to help its treatment (but it is based on low quality of evidence). The aims of this review are: highlight the importance of this problem in malnourished patients, discuss the pathophysiology and clinical characteristics, with a final series of recommendations to reduce the risk of the syndrome and facilitate the treatment.

Refeeding after caloric restriction reverses altered liver glucose release.

CONTEXT: Caloric restriction increases liver glucose release (LGR), but it is not known if this is a permanent condition. OBJECTIVE: To investigate if refeeding after caloric restriction reverses the high LGR. MATERIALS AND METHODS: Rats were organised in six-pups litters (GC); 12-pups litters with either 50% caloric restriction from 21 to 80 days of age (GR) or fed at will from 50 to 80 days of age (GRL). Liver perfusion was made at the age of 80 days. RESULTS: LGR was higher in the GR both during basal and adrenaline-stimulated conditions. Refeeding after caloric restriction decreased it to values close to those of GC rats. DISCUSSION: The altered LGR of GR rats was reversed by refeeding (group GRL). The influence of hypothalamic neuropetides on these hepatic changes is suggested. CONCLUSIONS: Enhanced LGR under caloric restriction is not programmed by early feeding; instead, it is determined by the current nutritional conditions.

Vitamin B1 in critically ill patients: needs and challenges.

BACKGROUND: Thiamine has a crucial role in energy production, and consequently thiamine deficiency (TD) has been associated with cardiac failure, neurological disorders, oxidative stress (lactic acidosis and sepsis) and refeeding syndrome (RFS). This review aims to explore analytical methodologies of thiamine compound quantification and highlight similarities, variances and limitations of current techniques and how they may be relevant to patients. CONTENT: An electronic search of Medline, PubMed and Embase databases for original articles published in peer-reviewed journals was conducted. MethodsNow was used to search for published analytical methods of thiamine compounds. Keywords for all databases included "thiamine and its phosphate esters", "thiamine methodology" and terms related to critical illness. Enquiries were also made to six external quality assurance (EQA) programme organisations for the inclusion of thiamine measurement. SUMMARY: A total of 777 published articles were identified; 122 were included in this review. The most common published method is HPLC with florescence detection. Two of the six EQA organisations include a thiamine measurement programme, both measuring only whole-blood thiamine pyrophosphate (TPP). No standard measurement procedure for thiamine compound quantification was identified. OUTLOOK: Overall, there is an absence of standardisation in measurement methodologies for thiamine in clinical care. Consequently, multiple variations in method practises are prohibiting the comparison of study results as they are not traceable to any higher order reference. Traceability of certified reference materials and reference measurement procedures is needed to provide an anchor to create the link between studies and help bring consensus on the clinical importance of thiamine.

NMR-Based Metabonomic Analysis of Physiological Responses to Starvation and Refeeding in the Rat.

Starvation is a postabsorptive condition derived from a limitation on food resources by external factors. Energy homeostasis is maintained under this condition by using sources other than glucose via adaptive mechanisms. After refeeding, when food is available, other adaptive processes are linked to energy balance. However, less has been reported about the physiological mechanisms present as a result of these conditions, considering the rat as a supraorganism. Metabolic profiling using (1)H nuclear magnetic resonance spectroscopy was used to characterize the physiological metabolic differences in urine specimens collected under starved, refed, and recovered conditions. In addition, because starvation induced lack of faecal production and not all animals produced faeces during refeeding, 24 h pooled faecal water samples were also analyzed. Urinary metabolites upregulated by starvation included 2-butanamidoacetate, 3-hydroxyisovalerate, ketoleucine, methylmalonate, p-cresyl glucuronide, p-cresyl sulfate, phenylacetylglycine, pseudouridine, creatinine, taurine, and N-acetyl glycoprotein, which were related to renal and skeletal muscle function, ß-oxidation, turnover of proteins and RNA, and host-microbial interactions. Food-derived metabolites, including gut microbial cometabolites, and tricarboxylic acid cycle intermediates were upregulated under refed and recovered conditions, which characterized anabolic urinary metabotypes. The upregulation of creatine and pantothenate indicated an absorptive state after refeeding. Fecal short chain fatty acids, 3-(3-hydroxyphenyl)propionate, lactate, and acetoin provided additional information about the combinatorial metabolism between the host and gut microbiota. This investigation contributes to allow a deeper understanding of physiological responses associated with starvation and refeeding.

A role for adipose tissue de novo lipogenesis in glucose homeostasis during catch-up growth: a Randle cycle favoring fat storage.

Catch-up growth, a risk factor for type 2 diabetes, is characterized by hyperinsulinemia and accelerated body fat recovery. Using a rat model of semistarvation-refeeding that exhibits catch-up fat, we previously reported that during refeeding on a low-fat diet, glucose tolerance is normal but insulin-dependent glucose utilization is decreased in skeletal muscle and increased in adipose tissue, where de novo lipogenic capacity is concomitantly enhanced. Here we report that isocaloric refeeding on a high-fat (HF) diet blunts the enhanced in vivo insulin-dependent glucose utilization for de novo lipogenesis (DNL) in adipose tissue. These are shown to be early events of catch-up growth that are independent of hyperphagia and precede the development of overt adipocyte hypertrophy, adipose tissue inflammation, or defective insulin signaling. These results suggest a role for enhanced DNL as a glucose sink in regulating glycemia during catch-up growth, which is blunted by exposure to an HF diet, thereby contributing, together with skeletal muscle insulin resistance, to the development of glucose intolerance. Our findings are presented as an extension of the Randle cycle hypothesis, whereby the suppression of DNL constitutes a mechanism by which dietary lipids antagonize glucose utilization for storage as triglycerides in adipose tissue, thereby impairing glucose homeostasis during catch-up growth.

Refeeding syndrome as an unusual cause of anion gap metabolic acidosis.

Refeeding syndrome is characterized by hypophosphatemia in the setting of malnutrition. It is commonly seen in patients with anorexia, alcoholism, or malignancy, and it is often a missed diagnosis. Because of the potential morbidity associated with missing the diagnosis of refeeding syndrome, it is important to monitor for this disease in any malnourished patient. We present a case of a 49-year-old male with chronic alcohol abuse who presented for alcohol detoxification and was found to have low phosphate, potassium, and magnesium on presentation, in addition to an elevated anion gap of unclear etiology. After extensive workup to evaluate the cause of his elevated anion gap and worsening of his electrolyte abnormalities despite replenishment, it was felt his symptoms were a result of refeeding syndrome. After oral intake was held and aggressive electrolyte replenishment was performed for 24 hours, the patient's anion gap closed and his electrolyte levels stabilized. This case demonstrates a unique presentation of refeeding syndrome given the patient's profound metabolic acidosis that provided a clue toward his eventual diagnosis. The standard workup for an anion gap metabolic acidosis was negative, and it was not until his refeeding syndrome had been treated that the anion gap closed.

Resveratrol improves insulin resistance of catch-up growth by increasing mitochondrial complexes and antioxidant function in skeletal muscle.

Caloric restriction followed by refeeding, a phenomenon known as catch-up growth (CUG), affects mitochondrial function and results in systemic insulin resistance (IR). We investigated the potential of resveratrol (RES) in CUG to prevent IR by increasing activity of the mitochondrial respiratory chain and antioxidant enzymes in skeletal muscle. Rats (8 weeks of age) were divided into 3 groups: normal chow, CUG, and CUG with RES intervention. Skeletal muscle and systemic IR were measured in each group after 4 and 8 weeks. Mitochondrial biogenesis and function, oxidative stress levels, and antioxidant enzyme activity in skeletal muscle were assessed. Catch-up growth-induced IR resulted in significant reductions in both average glucose infusion rate(60-120) at euglycemia and skeletal muscle glucose uptake. Mitochondrial citrate synthase activity was lower; and the activity of complexes I to IV in the intermyofibrillar and subsarcolemmal (SS) mitochondria were reduced by 20% to 40%, with the decrease being more pronounced in the SS fraction. Reactive oxygen species levels were significantly higher in intermyofibrillar and SS mitochondria, whereas activities of antioxidant enzymes were decreased. Oral administration of RES, however, increased silent information regulator 1 activity and improved mitochondrial number and insulin sensitivity. Resveratrol treatment decreased levels of reactive oxygen species and restored activities of antioxidant enzymes. This study demonstrates that RES protects insulin sensitivity of skeletal muscle by improving activities of mitochondrial complexes and antioxidant defense status in CUG rats. Thus, RES has therapeutic potential for preventing CUG-related metabolic disorders.

Leptin and insulin growth factor 1: diagnostic markers of the refeeding syndrome and mortality.

Refeeding syndrome is difficult to diagnose since the guidelines for identifying those at risk are largely based on subjective clinical parameters and there are no predictive biochemical markers. We examined the suitability of insulin-like growth factor 1 (IGF1) and leptin as markers to identify patients at risk of the refeeding syndrome before initiation of parenteral nutrition (PN). A total of thirty-five consecutive patients referred for commencement of PN were included. Serum leptin and IGF1 were measured before starting PN. Electrolytes, liver and renal function tests were conducted before and daily for 1 week after initiating PN. The primary outcome was a decrease in phosphate 12-36 h after initiating PN. 'Refeeding index' (RI) was defined as leptin × IGF1 divided by 2800 to produce a ratio of 1·0 in patients who are well nourished. RI had better sensitivity (78 %; 95 % CI 40, 97 %) and specificity (78 %; 95 % CI 40, 97 %) with a likelihood ratio of 3·4, at a cut-off value of 0·19 for predicting a ≥ 30 % decrease in phosphate concentration within 12-36 h after starting PN, compared with IGF1 or leptin alone. However, IGF1 was a better predictor of mortality than either leptin or the RI. The present study is the first to derive and test the 'RI', and find that it is a sensitive and specific predictor of the refeeding syndrome in hospitalised patients before starting PN.

Refeeding syndrome.

Refeeding syndrome (RFS) is the result of aggressive enteral or parenteral feeding in a malnourished patient, with hypophosphatemia being the hallmark of this phenomenon. Other metabolic abnormalities, such as hypokalemia and hypomagnesemia, may also occur, along with sodium and fluid retention. The metabolic changes that occur in RFS can be severe enough to cause cardiorespiratory failure and death. This article reviews the pathophysiology, the clinical manifestations, and the management of RFS. The key to prevention is identifying patients at risk and being aware of the potential complications involved in rapidly reintroducing feeds to a malnourished patient.