Lipid stimulation of fatty acid sensors in the human duodenum: relationship with gastrointestinal hormones, BMI and diet.

BACKGROUND AND AIMS: The small intestinal free fatty acid (FFA) sensors, FFA receptor 1 (FFAR1), FFAR4, G-protein receptor 119 (GPR119) and cluster of differentiation-36 (CD36), mediate the fat-induced release of gastrointestinal (GI) hormones. We investigated whether expression of duodenal FFA sensors in humans was (i) altered by intraduodenal (ID) lipid infusion, (ii) disordered in overweight or obese individuals, (iii) related to lipid-induced GI hormone secretion or (iv) affected by habitual dietary patterns. METHODS: Endoscopic duodenal biopsies were collected from 20 lean (body mass index (BMI): 22±1 kg m-2), 18 overweight (BMI: 27±1 kg m-2) and 19 obese (BMI: 35±1 kg m-2) participants at baseline, and following a 30 min ID Intralipid infusion (2 kcal min-1); FFA sensor expression was quantified by reverse transcription-PCR. On a separate day, participants underwent ID Intralipid infusion (2 kcal min-1) for 120 min, to assess GI hormone responses. Habitual diet was evaluated using food frequency questionnaires. RESULTS: Baseline FFAR1 and FFAR4 expression were lower, and CD36 was higher, in obese participants compared with lean participants. ID lipid increased GPR119 and FFAR1 expression equally across study groups, but did not alter FFAR4 or CD36 expression. Increased FFAR1 expression correlated positively with glucose-dependent insulinotropic polypeptide (GIP) secretion (r=0.3, P<0.05), whereas there was no relationship between habitual diet with the expression of FFA sensors. CONCLUSIONS: Obesity is associated with altered duodenal expression of FFAR1, FFAR4 and CD36, suggesting altered capacity for the sensing, absorption and metabolism, of dietary lipids. GPR119 and FFAR1 are early transcriptional responders to the presence of ID lipid, whereas FFAR1 may be an important trigger for lipid-induced GIP release in humans.

From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways.

The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a growing number of diseases. Evidence is now emerging that, through interactions with the gut-brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association between enteropathy and certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies.

Life history as a constraint on plasticity: developmental timing is correlated with phenotypic variation in birds.

Understanding why organisms vary in developmental plasticity has implications for predicting population responses to changing environments and the maintenance of intraspecific variation. The epiphenotype hypothesis posits that the timing of development can constrain plasticity-the earlier alternate phenotypes begin to develop, the greater the difference that can result amongst the final traits. This research extends this idea by considering how life history timing shapes the opportunity for the environment to influence trait development. We test the prediction that the earlier an individual begins to actively interact with and explore their environment, the greater the opportunity for plasticity and thus variation in foraging traits. This research focuses on life history variation across four groups of birds using museum specimens and measurements from the literature. We reasoned that greater phenotypic plasticity, through either environmental effects or genotype-by-environment interactions in development, would be manifest in larger trait ranges (bills and tarsi) within species. Among shorebirds and ducks, we found that species with relatively shorter incubation times tended to show greater phenotypic variation. Across warblers and sparrows, we found little support linking timing of flight and trait variation. Overall, our results also suggest a pattern between body size and trait variation, consistent with constraints on egg size that might result in larger species having more environmental influences on development. Taken together, our results provide some support for the hypothesis that variation in life histories affects how the environment shapes development, through either the expression of plasticity or the release of cryptic genetic variation.

Expression of taste molecules in the upper gastrointestinal tract in humans with and without type 2 diabetes.

OBJECTIVE: Nutrient feedback from the small intestine modulates upper gastrointestinal function and energy intake; however, the molecular mechanism of nutrient detection is unknown. In the tongue, sugars are detected via taste T1R2 and T1R3 receptors and signalled via the taste G-protein alpha-gustducin (G alpha(gust)) and the transient receptor potential ion channel, TRPM5. These taste molecules are also present in the rodent small intestine, and may regulate gastrointestinal function. SUBJECTS AND METHODS: Absolute transcript levels for T1R2, T1R3, G alpha(gust) and TRPM5 were quantified in gastrointestinal mucosal biopsies from subjects with and without type 2 diabetes; immunohistochemistry was used to locate G alpha(gust). Effects of luminal glucose on jejunal expression of taste molecules were also quantified in mice. RESULTS: T1R2, T1R3, G alpha(gust) and TRPM5 were preferentially expressed in the proximal small intestine in humans, with immunolabelling for G alpha(gust) localised to solitary cells dispersed throughout the duodenal villous epithelium. Expression of T1R2, T1R3, TRPM5 (all p<0.05) and G alpha(gust) (p<0.001) inversely correlated with blood glucose concentration in type 2 diabetes subjects but, as a group, did not differ from control subjects. Transcript levels of T1R2 were reduced by 84% following jejunal glucose perfusion in mice (p<0.05). CONCLUSIONS: Taste molecules are expressed in nutrient detection regions of the proximal small intestine in humans, consistent with a role in "tasting". This taste molecule expression is decreased in diabetic subjects with elevated blood glucose concentration, and decreased by luminal glucose in mice, indicating that intestinal "taste" signalling is under dynamic metabolic and luminal control.

Evolution of sex-biased maternal effects in birds. IV. Intra-ovarian growth dynamics can link sex determination and sex-specific acquisition of resources.

The evolutionary importance of maternal effects is determined by the interplay of maternal adaptations and strategies, offspring susceptibility to these strategies, and the similarity of selection pressures between the two generations. Interaction among these components, especially in species where males and females differ in the costs and requirements of growth, limits inference about the evolution of maternal strategies from their expression in the offspring phenotype alone. As an alternative approach, we examine divergence in the proximate mechanisms underlying maternal effects across three house finch populations with contrasting patterns of sex allocation: an ancestral population that shows no sex-biased ovulation, and two recently established populations at the northern and southern boundaries of the species range that have opposite sequences of ovulation of male and female eggs. For each population, we examined how oocyte acquisition of hormones, carotenoids and vitamins was affected by oocyte growth and overlap with the same and opposite sexes. Our results suggest that sex-specific acquisition of maternal resources and sex determination of oocytes are linked in this system. We report that acquisition of testosterone by oocytes that become males was not related to growth duration, but instead covaried with temporal exposure to steroids and overlap with other male oocytes. In female oocytes, testosterone acquisition increased with the duration of growth and overlap with male oocytes, but decreased with overlap with female oocytes. By contrast, acquisition of carotenoids and vitamins was mostly determined by organism-wide partitioning among oocytes and oocyte-specific patterns of testosterone accumulation, and these effects did not differ between the sexes. These results provide important insights into three unresolved phenomena in the evolution of maternal effects - (i) the evolution of sex-specific maternal allocation in species with simultaneously developing neonates of both sexes; (ii) the link between sex determination and sex-specific acquisition of maternal products; and (iii) the evolution of context-dependent modulation of maternal effects.

A negative regulatory element in the bcl-2 5'-untranslated region inhibits expression from an upstream promoter.

bcl-2 mRNA is present at high levels in pre-B-cell lines but is down-regulated in most mature B-cell lines. To investigate the mechanisms responsible for its developmental control, we studied the regulation of bcl-2 expression in human B-lineage cell lines. Using nuclear run-on assays, we found that bcl-2 transcription decreases in parallel with levels of steady-state mRNA during B-cell development. To define cis-acting elements that regulate bcl-2 transcription, we analyzed the expression of transiently transfected promoter-reporter constructs. We identified a novel negative regulatory element (NRE) in the bcl-2 5'-untranslated region that decreased expression from the bcl-2 P1 promoter or heterologous promoters in a position-dependent fashion. The NRE functions in either orientation but contains distinct orientation-dependent subfragments. Additional analyses demonstrated that multiple, functionally redundant sequence elements mediate NRE activity. Though the bcl-2 NRE is active in pre-B- and mature B-cell lines, chromatin structure of the endogenous NRE differs in these cells, suggesting that its activity or effect may vary during B-cell development. Our results indicate that negative control of transcription initiated at the P1 promoter is an important determinant of the differential expression of bcl-2.

The nutrient-sensing repertoires of mouse enterochromaffin cells differ between duodenum and colon.

BACKGROUND: Enterochromaffin (EC) cells within the gastrointestinal (GI) tract provide almost all body serotonin (5-hydroxytryptamine [5-HT]). Peripheral 5-HT, released from EC cells lining the gut wall, serves diverse physiological roles. These include modulating GI motility, bone formation, hepatic gluconeogenesis, thermogenesis, insulin resistance, and regulation of fat mass. Enterochromaffin cells are nutrient sensors, but which nutrients they are responsive to and how this changes in different parts of the GI tract are poorly understood. METHODS: To accurately undertake such an examination, we undertook the first isolation and purification of primary mouse EC cells from both the duodenum and colon in the same animal. This allowed us to compare, in an internally controlled manner, regional differences in the expression of nutrient sensors in EC cells using real-time PCR. KEY RESULTS: Both colonic and duodenal EC cells expressed G protein-coupled receptors and facilitative transporters for sugars, free fatty acids, amino acids, and lipid amides. We find differential expression of nutrient receptor and transporters in EC cells obtained from duodenal and colonic EC cells. Duodenal EC cells have higher expression of tryptophan hydroxylase-1, sugar transporters GLUT2, GLUT5, and free fatty acid receptors 1 and 3 (FFAR1 and FFAR3). Colonic EC cells express higher levels of GLUT1, FFAR2, and FFAR4. CONCLUSIONS & INFERENCES: We highlight the diversity of EC cell physiology and identify differences in the regional sensing repertoire of EC cells to an assortment of nutrients. These data indicate that not all EC cells are similar and that differences in their physiological responses are likely dependent on their location within the GI tract.

Glucose-insulin response to oral glucose in a healthy obese population.

The characteristics of the glucose and insulin responses during the glucose tolerance test (GTT) in obese people as a group have not been established. We analyzed glucose and insulin levels during GTT in 160 healthy obese patients who averaged 42% over ideal body weight. Statistical upper limit of normal for 2-h glucose was 260 mg/dl in women and 206 mg/dl in men. Although there was a significant correlation between insulin and glucose levels in both sexes and between insulin and degree of obesity in women, r values were relatively low (r less than 0.4 for all). High insulin levels and delayed peak insulin were present in the majority of patients with normal GTT and absent in many of the most obese patients. Results indicate that upper limits of normal glucose for GTT in the obese are much higher than currently accepted criteria.

T4-thyrotoxicosis.

A 41-year-old man had thyrotoxicosis, diffuse goiter, exophthalmos, high titer of antithyroglobulin antibodies but undetectable long-acting thyroid stimulator. Initially, he had both elevated serum thyroxine (T4) and reverse triiodothyronine (rT3) levels, but normal serum triiodothyronine (T3) and free triiodothyronine (FT3) levels and 24-hour radioactive iodine uptake. Observations prior to radioactive iodine therapy uptake. Observations prior to radioactive iodine therapy showed a persistently normal T3 level in spite of development of atrial fibrillation. Iodine excess was not present, nor were any drugs or systemic illnesses that cause preferential monodeiodination of T4 to rT3 instead of T3. The data support the concept that (1) thyroxine is not just a prohormone for triiodothyronine but is metabolically active itself; (2) Graves' disease can be a cause of T4-thyrotoxicosis. We conclude that a normal serum T3 level does not rule out thyrotoxicosis.

Propranolol as primary therapy for thyrotoxicosis.

It has been suggested that propranolol hydrochloride alone is effective in the treatment of thyrotoxicosis. To test this hypothesis, eight mildly thyrotoxic individuals were prospectively studied for an average of eight months, during which propranolol alone was administered and thyroid function tests, cardiac systolic time intervals, and body densities were sequentially measured. Two patients became euthyroid. The others had adequate but incomplete symptomatic control. Weight loss was not corrected, but no changes in lean body mass were induced. The augmented myocardial contractility of thyrotoxicosis, as determined by systolic time intervals, improved but failed to return completely to normal. Thus, systolic time intervals are a practical means of following the peripheral response to chronic beta-adrenergic blockage in thyrotoxic patients. However, these observations do not support the use of propranolol alone as the first choice of therapy for thyrotoxicosis.

Transient diabetes insipidus with elevated serum osmolarity associated with 'benign' febrile illness.

A 38-year-old physician developed polyuria and hypodipsia four days after the onset of an upper respiratory tract infection. Subsequent investigation showed a concentration defect with dehydration that partially corrected with vasopressin injection (Pitressin) administration compatible with partial central diabetes insipidus (DI). Skull roentgenograms, EEG, and lumbar puncture were normal. The polyuria and hypodipsia slowly resolved without treatment. Normal urinary concentration ability was achieved by the 48th day, but a residual elevation in serum osmolarity persisted for one year. Review of the literature failed to show previous documentation of transient DI with elevated serum osmolarity from an acute, febrile illness. The mechanism is speculative, but may be related to a subclinical encephalitis. The true frequency of this syndrome and its relationship to the frequent observation of transient polydipsia and polyuria in "benign" febrile illness remains to be determined.

Altered cardiac hormone and contractile protein messenger RNA levels following left ventricular myocardial infarction in the rat: an in situ hybridization histochemical study.

OBJECTIVES: Cardiac remodeling secondary to myocardial infarction is associated with hypertrophy of surviving myocardium and altered cardiac gene expression. The present study examined the spatiotemporal expression of cardiac contractile protein and peptide hormone mRNA following left ventricular myocardial infarction (LVMI) in the rat heart. METHODS: LVMI was produced in Wistar rats by ligation of the left anterior descending coronary artery and mRNA levels of cardiac alpha-action (sACT), ventricular myosin light chain-2(MLC-2v), beta-myosin heavy chain (beta-MHC) and pre-proatrial natriuretic peptide (ppANP) were examined at 24 h, 1 and 4 weeks) post-LVMI by in situ hybridization histochemistry with 35S-labeled oligonucleotide probes. RESULTS: Infarct size, determined at 1 week post-LVMI, was 44.5 +/- 2.7% of the combined left ventricular epi- and endocardial surface area. Myocyte fiber width, reflecting cellular hypertrophy, was increased in left ventricular, mid-septal and mid-right ventricular muscle fibers by 11-20% at 1 week post-LVMI (P < 0.05) and by 24-29% at 4 weeks (P < 0.05). At 24 h, 1 and 4 weeks post-LVMI, heart- and lung/body weight ratios were significantly elevated compared to sham-operated rats (1.3-1.8-fold, P < 0.01 and 1.6-2.9-fold, P < 0.005, respectively). PpANP mRNA levels in the left ventricle were increased 3.8- and 3.3-fold at 1 and 4 weeks (P < 0.05), with highest levels in the epicardium, papillary muscle, infundibulum and apex of the chamber. Septal and right ventricular ppANP mRNA levels were highest at 24 h post-LVMI (2.1- and 2.6-fold increase, P < 0.05) and remained elevated at 4 weeks, with maximum levels at the left endocardial surface of the septum and apex of the chambers. Atrial levels of cACT mRNA were increased 1.9-fold at 1 week post-LVMI (P < 0.05) and remained elevated at 4 weeks. Skeletal ACT mRNA, not normally expressed in the adult rat heart, was induced as early as 24 h post-LVMI in both atria, the septum and right ventricle, with discrete hybridization signal detected at the apex of the chambers and in the right ventricular free-wall, and later (1 week) in the left ventricular epicardium. MLC-2v mRNA levels were unaltered post-LVMI, except for a transitory loss of expression at 24 h in the left atria, ventricle and apical septum. In contrast, ventricular beta-MHC mRNA was markedly induced in regions containing increased ppANP mRNA, with a maximal 3.0- and 4.0-fold induction (P < 0.05) seen at 1 and 4 weeks in the left ventricle and a 3.7-fold induction at 4 weeks in the septum and right ventricle (P < 0.05). CONCLUSION: The regional increases in induced cardiac hormone and contractile protein mRNA in similar subchamber regions of the rat heart post-LVMI implies mutual activation by mechanical and/or neuroendocrine stimuli in the transcriptional response to myocardial overload.

Thyroid-stimulating hormone levels in idiopathic euthyroid goiter.

Utilizing a double antibody radioimmunoassay for human TSH we compared distribution of serum TSH in 167 normal individuals and 51 patients with idiopathic euthyroid goiter. In addition to being clinically euthyroid both groups had normal total thyroxine, and free thyroid index. Forty-two percent of the goiter group had high TSH and the general distribution of TSH values in the goiterous patients was significantly higher than normal (P less than 0.001). Anlysis of subgroups of the normal and goiter populations indicated that the high TSH could not be attributed to age, sex, use of birth control pills or differences between diffuse and multinodular goiter. TSH levels were significantly higher in patients with goiter less than 1 yr compared to goiter greater than 1 yr (P less than 0.025). In patients with goiter greater than 1 yr the TSH levels remained significantly higher than normal (P less than 0.025). These results support the hypothesis that TSH plays a role in the genesis of idiopathic goiter. The elevation may be present only early in the course of goiter development but is also present in a significant number of patients with long standing goiter.

Cholelithiasis in patients treated with a very-low-calorie diet.

One hundred seventy-nine obese patients (mean body mass index = 36.3) were retrospectively evaluated for the development of cholelithiasis associated with the use of a 2530-kJ/d (605-kcal) very-low-calorie diet (VLCD). Nine percent of patients had preexisting gallstones and 11% of patients developed gallstones either during or within 6 mo of completing the diet. Six percent had subsequent cholecystectomy. Ursodeoxycholic acid administered to one patient resulted in spontaneous stone dissolution whereas spontaneous dissolution occurred in three patients. Surveys of patients at three other programs using the same diet yielded similar incidence of gallstones. We conclude that rapid weight loss associated with the use of VLCD is associated with a significant incidence of gallstone formation. VLCD should be physician supervised because resolution of cholelithiasis spontaneously, with stone passage, or dissolution with ursodeoxycholic acid therapy may reduce the need for cholecystectomy.

Papillary thyroid carcinoma: a 10 year follow-up report of the impact of therapy in 576 patients.

Data from 576 patients with papillary thyroid cancer were retrospectively analyzed. With a median follow-up of 10 years and three months, there were six deaths from, and 84 recurrences of, thyroid cancer. Of the latter, 16 (19 percent) could not be eradicated. Death from thyroid cancer occurred only in those 30 years of age or over at the time of diagnosis and only in patients with primary tumors larger than 1.5 cm in diameter. Locally invasive tumor was associated with a poor prognosis. Cervical lymph node metastases found at initial surgery were associated with higher recurrence rates but not higher mortality rates. Treatment with total thyroidectomy, postoperative radioiodine and thyroid hormone resulted in the lowest recurrence and mortality rates except in those patients with small primary tumors (less than 1.5 cm diameter) in whom less than total thyroidectomy and postoperative therapy with thyroid hormone alone gave results which did not differ statistically from those achieved with more aggressive therapy. No important differences in outcome were observed when cervical lymph node metastases were simply excised or more aggressively treated by neck dissection. External radiation and as initial adjunctive therapy adversely influenced outcome.

Clinical manifestations of polycystic ovarian disease.

Elevated androgens and/or increased sensitivity to them is at the core of polycystic ovarian disease (PCOD). In orbit around this essential element are a wide variety of signs and symptoms that may come into alignment in unpredictable fashion and frequency. This article considers the clinical history and physical examination of the patient with PCOD, ovarian morphology, the laboratory work-up of patients with PCOD, and the role of ultrasonography, magnetic resonance imaging, and laparoscopy in the diagnosis of PCOD.

Selected aspects of polycystic ovarian disease.

Although there is general agreement about the polycystic ovary as an anatomic entity, a classic description of an associated syndrome remains elusive. This lack of definition, however, has not impeded clinical investigation. This article focuses on the diagnosis, pathogenesis, hypotheses, and treatment of polycystic ovarian disease.

PIP: Ultrasonography provides physicians much information for the epidemiology and diagnosis of polycystic ovarian disease (PCOD)--a yet to be defined associated syndrome. For example, some physicians used it to reveal that 92% of women with hirsutism and regular menstrual cycles had PCOD. Considerable research exists on the link between insulin resistance. PCOD, and hyperandrogenism. Some results confirm the link while others do not. Abnormal gonadotropin dynamics are 1 of the most consistent characteristics of PCOD. Researchers have conceived various hypotheses for PCOD. A long-lived hypothesis is that elevated estrone levels which occur regularly in PCOD increase the sensitization of pituitary luteinizing hormone (LH) secretion and reduces secretion of follicle stimulating hormone to the gonadotropin releasing hormone stimulus. Another hypothesis is that progesterone deficiency facilitates PCOD. Various PCOD treatments exist. Physicians have treated PCOD with clomiphene citrate or nighttime small doses of corticosteroids for 20-30 years. Recent observations indicate the dexamethasone has a longer half life than prednisone or prednisolone. Since almost 50% of women with PCOD are obese, weight reduction has beneficial effects. Administration of progesterone is a possible treatment that is often ignored. Several clinical studies have included administration of bromocriptine to women with PCOD since a sizable number of such women have high levels of prolactin indicating a possible dopamine deficiency. The studies with bromocriptine have not showed much promise. Evidence suggests that administering oral contraceptives to premenopausal women with PCOD may reduce their risk of later developing ovarian cancer. Gonadotropin and gonadotropin releasing hormone therapies are possible means of inducing ovulation in PCOD women. Various physicians have used laparoscopy to apply different techniques to induce ovulation in women with PCOD. These techniques included sharp puncture, electric current, and laser vaporization or endocoagulation of the cysts.

The increasing incidence of hypothyroidism within one year after radioiodine therapy for toxic diffuse goiter.

Patients treated with 10 mCi of I-131 for toxic diffuse goiter in the period January 1974--June 1976 were evaluated for development of hypothyroidism. Fifty percent were hypothyroid within 3 mo and 69% within 1 yr of treatment. Our data suggest that there is a higher incidence of hypothyroidism after standard doses of I-131 in the 1970s as contrasted with treatment groups in the 1950s and 1960s. The pathophysiology of this increased incidence is not known with certainty; however, infrequent use of thionamide medication, together with recent increases in dietary iodine, may render the gland more radiosensitive.

Pure follicular thyroid carcinoma: impact of therapy in 214 patients.

Records of 214 patients with pure follicular thyroid carcinoma were reviewed in detail to evaluate the circumstances of initial presentation and therapy on ultimate outcome. Mean followup was 8.8 yr. The only deaths directly attributable to the thyroid carcinoma occurred in patients with distant metastases at the time of presentation. There were 20 recurrences in the 182 patients considered free of disease after initial therapy. Overall recurrence rate was not affected by the presence of positive cervical nodes or extent of thyroid surgery. Postoperative recurrence rate was decreased by both radioiodine and thyroid-hormone therapy. Extensive histologic invasion of the capsule of the nodule and thyroid appeared to be associated with an increase in recurrence rate. Postoperative thyroid-hormone is required therapy in all patients with pure follicular thyroid carcinoma. Radioiodine therapy is indicated in patients with extensive invasion and we favor its use in all patients.

The treatment of benign thyroid disease.

The treatment of benign forms of thyroid disease is reviewed. Endemic goiter is a public health problem preventable by the addition of iodine to the food or water supply. Endemic and familial goiters are treated with replacement doses of I-thyroxine, as are sporadic colloid goiters and goiters resulting from chronic thyroiditis. Hyperfunctioning autionomous nodules without thyrotoxicosis and cystic nodules require no specific therapy. Prophylaxis against diffuse or nodular goiter after radiation to the head or neck for therapeutic purposes with thyroxine replacement therapy is debatable. All forms of hypothyroidism, including incipient types, require replacement thyroxine therapy, but this should be undertaken cautiously in older patients and in those with evidence of ischemic myocardial disease. Myxedema coma requires vigorous treatment and detailed supervision because of dismal mortality rates. Iodine 131 is the treatment of choice in diffuse toxic goiter, but alternative forms.