Maternal adaptations of the pancreas and glucose homeostasis in lactation and after lactation.

During lactation, the maternal physiology adapts to bear the nutritional requirements of the offspring. The exocrine and endocrine pancreas are central to nutrient handling, promoting digestion and metabolism. In concert with prolactin, insulin is a determinant factor for milk synthesis. The investigation of the pancreas during lactation has been scattered over several periods. The investigations that laid the foundation of lactating pancreatic physiology and glucose homeostasis were conducted in the decades of 1970-1980. With the development of molecular biology, newer studies have revealed the molecular mechanisms involved in the endocrine pancreas during breastfeeding. There has been a surge of information recently about unexpected changes in the pancreas at the end of the lactation period and after weaning. In this review, we aim to gather information on the changes in the pancreas and glucose homeostasis during and after lactation and discuss the outcomes derived from the current discoveries.

Maternal adaptations of pancreatic islets and glucose metabolism after lactation.

Pancreatic islets adapt to metabolic requirements and the hormonal milieu by modifying their size and hormone secretions. Maternal glucose demands and hormonal changes occur after weaning, to rapidly re-establish bone mineralization. Minimal information exists about glucose metabolism and pancreatic islets after lactation. This study investigated islet morphology and glucose homeostasis for 14 days after lactation in C57BL/6NHHsd mice. Compared to the day of weaning, rapid increases in the islets' area and number of beta cells were found from the first day post-lactation, attaining maximum values on the third day post-weaning. These changes were accompanied by modifications in glucose-induced insulin secretion, glucose tolerance and insulin sensitivity. Islet-cell proliferation was already augmented before lactation ceased. Serum undercarboxylated osteocalcin concentrations increased significantly post-lactation; however, it is unlikely that this enhancement participates in earlier cell proliferation augmentation or in decreasing insulin sensitivity. Islet serotonin content was barely expressed, and serum calcium concentrations decreased. By the 14th day post-weaning, islets' area and glucose homeostasis returned to age-matched virgin mice levels. These findings recognize for the first time that increases in islet area and insulin secretion occur during physiological post-weaning conditions. These results open up new opportunities to identify molecules and mechanisms participating in these processes, which will help in developing strategies to combat diabetes.

Early-life programming of adipose tissue.

Worldwide obesity is increasing at an alarming rate in children and adolescents, with the consequent emergence of co-morbidities. Moreover, the maternal environment during pregnancy plays an important role in obesity, contributing to transgenerational transmission of the same and metabolic dysfunction. White adipose tissue represents a prime target of metabolic programming induced by maternal milieu. In this article, we review adipose tissue physiology and development, as well as maternal influences during the perinatal period that may lead to obesity in early postnatal life and adulthood. First, we describe the adipose tissue cell composition, distribution and hormonal action, together with the evidence of hormonal factors participating in fetal/postnatal programming. Subsequently, we describe the critical periods of adipose tissue development and the relationship of gestational and early postnatal life with healthy fetal adipose tissue expansion. Furthermore, we discuss the evidence showing that adipose tissue is an important target for nutritional, hormonal and epigenetic signals to modulate fetal growth. Finally, we describe nutritional, hormonal, epigenetic and microbiome changes observed in maternal obesity, and whether their disruption alters fetal growth and adiposity. The presented evidence supports the developmental origins of health and disease concept, which proposes that the homeostatic system is affected during gestational and postnatal development, impeding the ability to regulate body weight after birth, thereby resulting in adult obesity. Consequently, we anticipate that promoting a healthy early-life programming of adipose tissue and increasing the knowledge of the mechanisms by which maternal factors affect the health of future generations may offer novel strategies for explaining and addressing worldwide health problems such as obesity.

Dietary Biotin Supplementation Impairs Testis Morphology and Sperm Quality.

Supplements containing pharmacological concentrations of biotin are commercially available over the counter. Classical toxicity studies have considered biotin administration as harmless; however, recent investigations have shown that biotin supplementation modifies tissue morphology without changes in toxicity markers, raising concerns about the consequences of morphological changes on tissues' functions and the safety of pharmacological concentrations of the vitamin. Testes are very sensitive to toxicants, and testicular histology is a reliable method to study its function. In this work, we investigated the effects of dietary biotin supplementation on testis morphology and spermatogenesis function using an experimental model, in which we have not observed unfavorable effects on other tissue functions or toxicity markers. Male BALB/cAnNHsd mice were fed a control or a biotin-supplemented diet (1.76 or 97.7 mg biotin/kg diet) for 8 weeks. Compared to the control group, the biotin-supplemented mice presented remarkable testis morphology changes, including increased spermatogonia layers; the cellular mechanism involved is related to increased proliferation. Sperm count and serum testosterone levels were not affected, but spermatozoa motility and morphology were significantly impaired in the biotin-supplemented mice. These results caution against the use of supplements with high concentrations of biotin and indicate that biotin's pharmacological effects on morphology need to be considered in toxicological studies.

Morphological, hormonal, and molecular changes in different maternal tissues during lactation and post-lactation.

Milk supply and quality during lactation are critical for progeny survival. Maternal tissues and metabolism, influenced by hormonal changes, undergo modification during lactation to sustain breastfeeding. Two organs that suffer essential adjustment are the mammary glands and the bone; however, renal calcium conservation and calcium absorption from the intestine are also modified. Lactation leads to a transient loss of bone minerals to provide adequate amounts of minerals, including calcium for milk production. Physiological, metabolic, and molecular changes in different tissues participate in providing nutrients for milk production. After weaning, the histological, metabolic, and hormonal modifications that take place in lactation are reverted, and bone remineralization is a central function at this time. This study focuses on the hormonal, metabolic, molecular, and tissue modifications that occur in mammary glands, bone, intestine, and kidneys in the mother during lactation and post-weaning periods.

Effect of biotin supplementation on fatty acid metabolic pathways in 3T3-L1 adipocytes.

Several studies have shown that pharmacological concentrations of biotin decrease serum lipid concentrations and the expression of lipogenic genes. Previous studies on epididymal adipose tissue in mice revealed that 8 weeks of dietary biotin supplementation increased the protein abundance of the active form of AMPK and the inactive forms acetyl CoA carboxylase (ACC)-1 and - 2, and decreased serum free fatty acid concentrations but did not affect lipolysis. These data suggest that pharmacological concentrations of the vitamin might affect fatty acid metabolism. In this work, we investigated the effects of pharmacological biotin concentrations on fatty acid synthesis, oxidation, and uptake in 3T3-L1 adipocytes. Similar to observations in mice, biotin-supplemented 3T3-L1 adipose cells increased the protein abundance of active T172 -AMPK and inactive ACC-1 and -2 forms. No changes were observed in the expression of the transcriptional factor PPARα and carnitine-palmitoyltransferase-1 (CPT-1). Radiolabeled assays indicated a decrease in fatty acid synthesis; an increase in fatty acid oxidation and fatty acid incorporation rate into the lipid fraction between control cells and biotin-supplemented cells. The data revealed an increase in the mRNA abundance of the fatty acid transport proteins Fatp1 and Acsl1 but not Cd36 or Fatp4 mRNA. Furthermore, the abundance of glycerol phosphate acyl transferase-3 protein was increased. Triglyceride content was not affected. Lipid droplet numbers showed an increase and their areas were smaller in the biotin-supplemented group. In conclusion, these data indicate that biotin supplementation causes a decrease in fatty acid synthesis and an increase in its oxidation and uptake. © 2018 BioFactors, 45(2):259-270, 2019.

Effects of Biotin Supplementation During the First Week Postweaning Increases Pancreatic Islet Area, Beta-Cell Proportion, Islets Number, and Beta-Cell Proliferation.

During maturation, pancreatic islets achieve their full capacity to secrete insulin in response to glucose, undergo morphological changes in which alpha-cells decrease and beta-cell mass increases, and they acquire the normal alpha- and beta-cell proportion changes that are important for islet functions later in life. In rodents, the first week of postweaning is critical for islet maturation. Multiple studies have documented the detrimental effects of several conditions on pancreatic maturation; however, few studies have addressed the use of pharmacological agents to enhance islet maturation. Biotin might have a potential action on islet maturation. Pharmacological concentrations of biotin have been found to modify islet morphology and function. In a previous study, we found that mice fed a biotin-supplemented diet for 8 weeks after weaning showed an increase in basal and glucose stimulated insulin secretion, enlarged islet size, and modified islet structure. In the present study, we investigated the effect of biotin on maturation features during the first week postweaning. Female BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet for 1 week after weaning. Compared with the control, biotin-supplemented mice showed an increase in pancreatic islet number and area in addition to an augmented proportion of beta-cells in the islet. These effects were related to an increase in beta-cell proliferation. No differences were found in insulin secretion, blood glucose concentrations, or serum insulin levels. These results indicate that biotin supplementation is capable of affecting beta-cell proliferation and might be a therapeutic agent for establishing strategies for regenerative medicine.

Effects of dietary biotin supplementation on glucagon production, secretion, and action.

OBJECTIVE: Despite increasing evidence that pharmacologic concentrations of biotin modify glucose metabolism, to our knowledge there have not been any studies addressing the effects of biotin supplementation on glucagon production and secretion, considering glucagon is one of the major hormones in maintaining glucose homeostasis. The aim of this study was to investigate the effects of dietary biotin supplementation on glucagon expression, secretion, and action. METHODS: Male BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet (1.76 or 97.7 mg biotin/kg diet) for 8 wk postweaning. Glucagon gene mRNA expression was measured by the real-time polymerase chain reaction. Glucagon secretion was assessed in isolated islets and by glucagon concentration in plasma. Glucagon action was evaluated by glucagon tolerance tests, phosphoenolpyruvate carboxykinase (Pck1) mRNA expression, and glycogen degradation. RESULTS: Compared with the control group, glucagon mRNA and secretion were increased from the islets of the biotin-supplemented group. Fasting plasma glucagon levels were higher, but no differences between the groups were observed in nonfasting glucagon levels. Despite the elevated fasting glucagon levels, no differences were found in fasting blood glucose concentrations, fasting/fasting-refeeding glucagon tolerance tests, glycogen content and degradation, or mRNA expression of the hepatic gluconeogenic rate-limiting enzyme, Pck1. CONCLUSIONS: These results demonstrated that dietary biotin supplementation increased glucagon expression and secretion without affecting fasting blood glucose concentrations or glucagon tolerance and provided new insights into the effect of biotin supplementation on glucagon production and action.

Pharmacological Effects of Biotin in Animals.

In recent decades, it was found that vitamins affect biological functions in ways other than their long-known functions; niacin is the best example of a water-soluble vitamin known to possess multiple actions. Biotin, also known as vitamin B7 or vitamin H, is a water-soluble B-complex vitamin that serves as a covalently-bound coenzyme of carboxylases. It is now well documented that biotin has actions other than participating in classical enzyme catalysis reactions. Several lines of evidence have demonstrated that pharmacological concentrations of biotin affect glucose and lipid metabolism, hypertension, reproduction, development, and immunity. The effect of biotin on these functions is related to its actions at the transcriptional, translational, and post-translational levels. The bestsupported mechanism involved in the genetic effects of biotin is the soluble guanylate cyclase/protein kinase G (PKG) signaling cascade. Although there are commercially-available products containing pharmacological concentrations of biotin, the toxic effects of biotin have been poorly studied. This review summarizes the known actions and molecular mechanisms of pharmacological doses of biotin in animals and current information regarding biotin toxicity.

Dietary Biotin Supplementation Modifies Hepatic Morphology without Changes in Liver Toxicity Markers.

Pharmacological concentrations of biotin have pleiotropic effects. Several reports have documented that biotin supplementation decreases hyperglycemia. We have shown that a biotin-supplemented diet increased insulin secretion and the mRNA abundance of proteins regulating insulin transcription and secretion. We also found enlarged pancreatic islets and modified islet morphology. Other studies have shown that pharmacological concentrations of biotin modify tissue structure. Although biotin administration is considered safe, little attention has been given to its effect on tissue structure. In this study, we investigated the effect of biotin supplementation on hepatic morphology and liver toxicity markers. Male BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet for 8 weeks. Versus the control mice, biotin-supplemented mice had an altered portal triad with dilated sinusoids, increased vascularity, and bile conducts. Furthermore, we observed an increased proportion of nucleomegaly and binucleated hepatocytes. In spite of the liver morphological changes, no differences were observed in the serum liver damage indicators, oxidative stress markers, or antioxidant enzymes. Our data demonstrate for the first time that biotin supplementation affects liver morphology in normal mice, and that these modifications are not paralleled with damage markers.

Effects of Biotin Supplementation in the Diet on Adipose Tissue cGMP Concentrations, AMPK Activation, Lipolysis, and Serum-Free Fatty Acid Levels.

Several studies have shown that pharmacological concentrations of biotin decrease hyperlipidemia. The molecular mechanisms by which pharmacological concentrations of biotin modify lipid metabolism are largely unknown. Adipose tissue plays a central role in lipid homeostasis. In the present study, we analyzed the effects of biotin supplementation in adipose tissue on signaling pathways and critical proteins that regulate lipid metabolism, as well as on lipolysis. In addition, we assessed serum fatty acid concentrations. Male BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet (control: 1.76 mg biotin/kg; supplemented: 97.7 mg biotin/kg diet) over 8 weeks postweaning. Compared with the control group, biotin-supplemented mice showed an increase in the levels of adipose guanosine 3',5'-cyclic monophosphate (cGMP) (control: 30.3±3.27 pmol/g wet tissue; supplemented: 49.5±3.44 pmol/g wet tissue) and of phosphorylated forms of adenosine 5'-monophosphate-activated protein kinase (AMPK; 65.2%±1.06%), acetyl-coenzyme A (CoA), carboxylase-1 (196%±68%), and acetyl-CoA carboxylase-2 (78.1%±18%). Serum fatty acid concentrations were decreased (control: 1.12±0.04 mM; supplemented: 0.91±0.03 mM), and no change in lipolysis was found (control: 0.29±0.05 µmol/mL; supplemented: 0.33±0.08 µmol/mL). In conclusion, 8 weeks of dietary biotin supplementation increased adipose tissue cGMP content and protein expression of the active form of AMPK and of the inactive forms of acetyl-CoA carboxylase-1 and acetyl-CoA carboxylase-2. Serum fatty acid levels fell, and no change in lipolysis was observed. These findings provide insight into the effects of biotin supplementation on adipose tissue and support its use in the treatment of dyslipidemia.

Hepatic diseases related to triglyceride metabolism.

Triglycerides participate in key metabolic functions such as energy storage, thermal insulation and as deposit for essential and non-essential fatty acids that can be used as precursors for the synthesis of structural and functional phospholipids. The liver is a central organ in the regulation of triglyceride metabolism, and it participates in triglyceride synthesis, export, uptake and oxidation. The metabolic syndrome and associated diseases are among the main concerns of public health worldwide. One of the metabolic syndrome components is impaired triglyceride metabolism. Diseases associated with the metabolic syndrome promote the appearance of hepatic alterations e.g., non-alcoholic steatosis, steatohepatitis, fibrosis, cirrhosis and cancer. In this article, we review the molecular actions involved in impaired triglyceride metabolism and its association with hepatic diseases. We discuss mechanisms that reconcile the chronic inflammation and insulin resistance, and new concepts on the role of intestinal micro-flora permeability and proliferation in fatty liver etiology. We also describe the participation of oxidative stress in the progression of events leading from steatosis to steatohepatitis and fibrosis. Finally, we provide information regarding the mechanisms that link fatty acid accumulation during steatosis with changes in growth factors and cytokines that lead to the development of neoplastic cells. One of the main medical concerns vis-a-vis hepatic diseases is the lack of symptoms at the onset of the illness and, as result, its late diagnosis. The understandings of the molecular mechanisms that underlie hepatic diseases could help design strategies towards establishing markers for their accurate and timely diagnosis.

The hypotriglyceridemic effect of biotin supplementation involves increased levels of cGMP and AMPK activation.

In addition to its role as a carboxylase cofactor, biotin modifies gene expression and has manifold effects on systemic processes. Several studies have shown that biotin supplementation reduces hypertriglyceridemia. We have previously reported that this effect is related to decreased expression of lipogenic genes. In the present work, we analyzed signaling pathways and posttranscriptional mechanisms involved in the hypotriglyceridemic effects of biotin. Male BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet (1.76 or 97.7 mg of free biotin/kg diet, respectively for 8 weeks after weaning. The abundance of mature sterol regulatory element-binding protein (SREBP-1c), fatty-acid synthase (FAS), total acetyl-CoA carboxylase-1 (ACC-1) and its phosphorylated form, and AMP-activated protein kinase (AMPK) were evaluated in the liver. We also determined the serum triglyceride concentrations and the hepatic levels of triglycerides and cyclic GMP (cGMP). Compared to the control group, biotin-supplemented mice had lower serum and hepatic triglyceride concentrations. Biotin supplementation increased the levels of cGMP and the phosphorylated forms of AMPK and ACC-1 and decreased the abundance of the mature form of SREBP-1c and FAS. These data provide evidence that the mechanisms by which biotin supplementation reduces lipogenesis involve increased cGMP content and AMPK activation. In turn, these changes lead to augmented ACC-1 phosphorylation and decreased expression of both the mature form of SREBP-1c and FAS. Our results demonstrate for the first time that AMPK is involved in the effects of biotin supplementation and offer new insights into the mechanisms of biotin-mediated hypotriglyceridemic effects.

Effects of biotin deficiency on pancreatic islet morphology, insulin sensitivity and glucose homeostasis.

Several studies have revealed that physiological concentrations of biotin are required for the normal expression of critical carbohydrate metabolism genes and for glucose homeostasis. However, the different experimental models used in these studies make it difficult to integrate the effects of biotin deficiency on glucose metabolism. To further investigate the effects of biotin deficiency on glucose metabolism, we presently analyzed the effect of biotin deprivation on glucose homeostasis and on pancreatic islet morphology. Three-week-old male BALB/cAnN Hsd mice were fed a biotin-deficient or a biotin-control diet (0 or 7.2 µmol of free biotin/kg diet, respectively) over a period of 8 weeks. We found that biotin deprivation caused reduced concentrations of blood glucose and serum insulin concentrations, but increased plasma glucagon levels. Biotin-deficient mice also presented impaired glucose and insulin tolerance tests, indicating defects in insulin sensitivity. Altered insulin signaling was linked to a decrease in phosphorylated Akt/PKB but induced no change in insulin receptor abundance. Islet morphology studies revealed disruption of islet architecture due to biotin deficiency, and an increase in the number of α-cells in the islet core. Morphometric analyses found increased islet size, number of islets and glucagon-positive area, but a decreased insulin-positive area, in the biotin-deficient group. Glucagon secretion and gene expression increased in islets isolated from biotin-deficient mice. Our results suggest that biotin deficiency promotes hyperglycemic mechanisms such as increased glucagon concentration and decreased insulin secretion and sensitivity to compensate for reduced blood glucose concentrations. Variations in glucose homeostasis may participate in the changes observed in pancreatic islets.

Pharmacological concentrations of biotin reduce serum triglycerides and the expression of lipogenic genes.

Besides its role as a carboxylase prosthetic group, biotin regulates gene expression and has a wide repertoire of effects on systemic processes. Several studies have shown that pharmacological concentrations of biotin reduce hypertriglyceridemia. The molecular mechanisms by which pharmacological concentrations of biotin affect lipid metabolism are largely unknown. The present study analyzed the effects of pharmacological doses of biotin on triglyceridemia, insulin sensitivity and on mRNA expression of various lipogenic genes. Three-week-old male BALB/cAnN Hsd mice were fed a biotin-control or a biotin-supplemented diet (1.76 or 97.7mg of free biotin/kg diet, respectively) over a period of eight weeks. Serum triglyceride concentrations, insulin and glucose tolerance and mRNA abundance of various lipogenic genes were investigated. The biotin-supplemented group showed 35% less serum triglycerides than control mice. In the liver, we found a significant (P<0.05) reduction of mRNA levels of SREBP1-c, glucose transporter-2, phosphofructokinase-1, pyruvate kinase, acetyl-CoA carboxylase and fatty acid synthase, while glucose-6-phosphate dehydrogenase expression increased. No changes in glucokinase, stearoyl-CoA desaturase-1, FoxO1 or PPAR-gamma expression were observed. In adipose tissue, we found a decreased expression of SREBP1c, glucose-6-phosphate deshydrogenase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase-1, phosphofructokinase-1 and PPAR-gamma, but no changes in FoxO1 expression. Moreover, the group fed a biotin-supplemented diet showed a significant decrease in adipose tissue weight. No differences in insulin sensitivity or serum insulin concentrations were observed between groups. Our results indicate that pharmacological concentrations of biotin decrease serum tryglyceride concentrations and lipogenic gene expression in liver and adipose tissues.

Sex steroids effects on the endocrine pancreas.

The endocrine pancreas is central in the physiopathology of diabetes mellitus. Nutrients and hormones control endocrine pancreatic function and the secretion of insulin and other pancreatic islet hormones. Although the pancreas is not usually considered as a target of steroids, increasing evidence indicates that sex steroid hormones modify pancreatic islet function. The biological effects of steroid hormones are transduced by both, classical and non-classical steroid receptors that in turn produce slow genomic and rapid non-genomic responses. In this review, we focused on the effects of sex steroid hormones on endocrine pancreatic function, with special emphasis in animal studies.

Biotin increases glucokinase expression via soluble guanylate cyclase/protein kinase G, adenosine triphosphate production and autocrine action of insulin in pancreatic rat islets.

Besides its role as a carboxylase prosthetic group, biotin has important effects on gene expression. However, the molecular mechanisms through which biotin exerts these effects are largely unknown. We previously found that biotin increases pancreatic glucokinase expression. We have now explored the mechanisms underlying this effect. Pancreatic islets from Wistar rats were treated with biotin, in the presence or absence of different types of inhibitors. Glucokinase mRNA and 18s rRNA abundance were determined by real-time PCR. Adenosine triphosphate (ATP) content was analyzed by fluorometry. Biotin treatment increased glucokinase mRNA abundance approximately one fold after 2 h; the effect was sustained up to 24 h. Inhibition of soluble guanylate cyclase or protein kinase G (PKG) signalling suppressed biotin-induced glucokinase expression. The cascade of events downstream of PKG in biotin-mediated gene transcription is not known. We found that inhibition of insulin secretion with diazoxide or nifedipine prevented biotin-stimulated glucokinase mRNA increase. Biotin treatment increased islet ATP content (control: 4.68+/-0.28; biotin treated: 6.62+/-0.26 pmol/islet) at 30 min. Inhibition of PKG activity suppressed the effects of biotin on ATP content. Insulin antibodies or inhibitors of phosphoinositol-3-kinase/Akt insulin signalling pathway prevented biotin-induced glucokinase expression. The nucleotide 8-Br-cGMP mimicked the biotin effects. We propose that the induction of pancreatic glucokinase mRNA by biotin involves guanylate cyclase and PKG activation, which leads to an increase in ATP content. This induces insulin secretion via ATP-sensitive potassium channels. Autocrine insulin, in turn, activates phosphoinositol-3-kinase/Akt signalling. Our results offer new insights into the pathways that participate in biotin-mediated gene expression.

Biotin deficiency and biotin excess: effects on the female reproductive system.

Biotin deficiency and biotin excess have both been found to affect reproduction and cause teratogenic effects. In the reproductive tract, however, the effects of biotin have not been well established yet. We investigated the effects of varying biotin content diets on the oestrus cycle, ovarian morphology, estradiol and progesterone serum levels, and the uterine mRNA abundance of their nuclear receptors, as well as on the activity of the estradiol-degrading group of enzymes cytochrome P450 (CYP) in the liver. Three-week-old female BALB/cAnN Hsd mice were fed a biotin-deficient, a biotin-control, or a biotin-supplemented diet (0, 7.2 or 400 micromol of free biotin/kg diet, respectively) over a period of nine weeks. Striking effects were observed in the biotin-deficient group: mice showed arrested estrous cycle on the day of diestrus and changes in ovary morphology. Estradiol serum concentration increased 49.2% in biotin-deficient mice compared to the control group, while the enzymatic activities of CYP1A2 and CYP2B2 increased (P<0.05). The mRNA abundance of nuclear estrogen and progesterone receptors decreased in the biotin-deficient mice. In the biotin-supplemented group we found that, in spite of a significant (P<0.05) decrease in the number of primary and Graafian follicles and in CYP1A2 activities, mice exhibited 105.4% higher serum estradiol concentration than the control group. No changes in the expression of the nuclear receptors were observed. No significant differences were observed in serum progesterone among the groups. Our results indicate that both the deficiency and the excess of biotin have significant effects on the female mouse reproductive system.

Biotin deficiency in mice is associated with decreased serum availability of insulin-like growth factor-I.

BACKGROUND: Biotin deficiency leads to decreased weight and nose-rump length in mice. AIM OF THE STUDY: The mechanisms underlying this impairment in body growth are yet unclear. Biotin restriction, however, could affect the availability of growth hormone (GH) and/or insulin like growth factor-I (IGF-I) since both hormones control body growth. We then conducted a correlative study aimed at establishing whether biotin dietary restriction is associated with decreased GH/IGF-I serum concentrations. METHODS: Levels of GH and IGF-I were measured through ELISA in serum samples of male BALB/cAnN mice fed with: 1] standard chow diet (control diet); 2] 30% egg-white biotin-deficient diet; or 3] 30% egg-white diet supplemented with 16.4 micromol biotin per kilogram (biotin sufficient diet). Relative food consumption, as adjusted per gram of body weight, was also determined. GH and IGF-I measurements were taken individually for 20 weeks beginning at the postnatal week 3, when the animals started consuming the corresponding diets. In addition, femur's weight and longitudinal growth and the organization of its growth plate were all analyzed as indicators of GH/IGF-I function. RESULTS: No differences in relative food consumption were observed among the three groups of mice along the experimental period that was evaluated. IGF-I serum levels, but not GH ones, were decreased in biotin deficient mice. These animals also showed decreased femur's longitudinal growth, speed of lengthening and weight gain, as well as shorter and disorganized growth plates. CONCLUSIONS: This study shows that biotin dietary restriction is indeed associated with decreased availability of IGF-I and diminished long bone growth and elongation. These conditions could explain the impairment of longitudinal body growth previously reported in biotin deficient mice. Although cause-effect studies are still needed, we believe our results support the notion that biotin might modulate the availability of IGF-I.