Alex F. Muller

Surgical treatment of obesity

More than half of the European population are overweight (body mass index (BMI) O25 and !30 kg/m 2 ) and up to 30% are obese (BMIR30 kg/m 2 ). Being overweight and obesity are becoming endemic, particularly because of increasing nourishment and a decrease in physical exercise. Insulin resistance, type 2 diabetes, dyslipidemia, hypertension, cholelithiasis, certain forms of cancer, steatosis hepatis, gastroesophageal reflux, obstructive sleep apnea, degenerative joint disease, gout, lower back pain, and polycystic ovary syndrome are all associated with overweight and obesity. The endemic extent of overweight and obesity with its associated comorbidities has led to the development of therapies aimed at weight loss. The long-term effects of diet, exercise, and medical therapy on weight are relatively poor. With respect to durable weight reduction, bariatric surgery is the most effective long-term treatment for obesity with the greatest chances for amelioration and even resolution of obesity-associated complications. Recent evidence shows that bariatric surgery for severe obesity is associated with decreased overall mortality. However, serious complications can occur and therefore a careful selection of patients is of utmost importance. Bariatric surgery should at least be considered for all patients with a BMI of more than 40 kg/m 2 and for those with a BMI of more than 35 kg/m 2 with concomitant obesity-related conditions after failure of conventional treatment. The importance of weight loss and results of conventional treatment will be discussed first. Currently used operative treatments for obesity and their effectiveness and complications are described. Proposed criteria for bariatric surgery are given. Also, some attention is devoted to more basic insights that bariatric surgery has provided. Finally we deal with unsolved questions and future directions for research.More than half of the European population are overweight (body mass index (BMI) > 25 and < 30 kg/m2) and up to 30% are obese (BMI > or = 30 kg/m2). Being overweight and obesity are becoming endemic, particularly because of increasing nourishment and a decrease in physical exercise. Insulin resistance, type 2 diabetes, dyslipidemia, hypertension, cholelithiasis, certain forms of cancer, steatosis hepatis, gastroesophageal reflux, obstructive sleep apnea, degenerative joint disease, gout, lower back pain, and polycystic ovary syndrome are all associated with overweight and obesity. The endemic extent of overweight and obesity with its associated comorbidities has led to the development of therapies aimed at weight loss. The long-term effects of diet, exercise, and medical therapy on weight are relatively poor. With respect to durable weight reduction, bariatric surgery is the most effective long-term treatment for obesity with the greatest chances for amelioration and even resolution of obesity-associated complications. Recent evidence shows that bariatric surgery for severe obesity is associated with decreased overall mortality. However, serious complications can occur and therefore a careful selection of patients is of utmost importance. Bariatric surgery should at least be considered for all patients with a BMI of more than 40 kg/m2 and for those with a BMI of more than 35 kg/m2 with concomitant obesity-related conditions after failure of conventional treatment. The importance of weight loss and results of conventional treatment will be discussed first. Currently used operative treatments for obesity and their effectiveness and complications are described. Proposed criteria for bariatric surgery are given. Also, some attention is devoted to more basic insights that bariatric surgery has provided. Finally we deal with unsolved questions and future directions for research.

Human Recombinant Interleukin-1Beta and -Alpha, but Not Recombinant Tumor Necrosis Factor Alpha Stimulate ACTH Release from Rat Anterior Pituitary Cells in vitro in a Prostaglandin E2 and cAMP Independent Manner

The pituitary-adrenal axis is known to be stimulated during the acute-phase response. As cytokines play a central role in mediating the constellation of host response occurring during the acute-phase response it was of interest to assess the ability of cytokines to stimulate ACTH secretion from normal pituitary cells in culture. We used human recombinant interleukin-1 beta and -alpha (hrIL1 beta, hrIL1 alpha) and human recombinant tumor necrosis factor alpha (hrTNF alpha) to analyze the ability of these cytokines to induce ACTH secretion from normal rat anterior pituitary cells in culture. We also investigated the possible roles of prostaglandin E2 (PGE2) and cAMP in the cellular transduction mechanism. After 3 days of incubation primary cultures of rat anterior pituitary cells were stimulated for 24 h with either hrIL1 beta, hrIL1 alpha or hrTNF alpha alone or with the addition of dexamethasone or indomethacin. The culture media were analyzed for ACTH, PGE2 and cAMP content. At doses ranging from 0.03 to 30 nM, hrIL1 beta stimulated the release of ACTH and PGE2 in a dose-dependent manner. In contrast, at doses ranging from 3 to 60 nM, hrTNF alpha was unable to stimulate ACTH secretion although it stimulated PGE2 synthesis. Time-course experiments demonstrated that hrIL1 beta (3 nM) stimulates ACTH production over a period of 8, 16 and 24 h, but not after a period of 4 h. In these experiments, hrIL1 beta failed to cause any change in the secretions of growth hormone and luteinizing hormone.(ABSTRACT TRUNCATED AT 250 WORDS)

Dexamethasone treatment increases neuropeptide Y levels in rat hypothalamic neurones

Immunoreactive glucocorticoid receptors (GR) have previously been demonstrated in neuropeptide Y (NPY) neurones of the rat hypothalamus. To determine whether NPY synthesis is influenced by glucocorticoids, the effect of dexamethasone (DEX) on the levels of immunoreactive NPY in rat hypothalamic neurones was investigated in vivo and in vitro. Daily injections of DEX (0.1 mg/day) for 5 days increased the NPY content of the mediobasal hypothalamus in female rats by 117% (p less than 0.002). Primary cultures of hypothalamic neurones were also sensitive to the effect of glucocorticoids. Intracellular NPY levels were significantly increased (p less than 0.001) compared to control values by 151%, 222% and 268% when cultures were maintained in a defined serum free medium containing DEX 10(-9), 10(-8) and 10(-7) M respectively.

Regional distribution of neuropeptide Y-like immunoreactivity in human hypothalamus measured by immunoradiometric assay: possible influence of chronic respiratory failure on tissue levels.

The regional distribution of neuropeptide Y-like immunoreactivity (NPY-IR) in the human hypothalamus has been determined using a highly specific immunoradiometric assay. Hypothalami were removed during postmortem examination from 19 subjects. The pituitary stalk and 11 anatomically defined nuclei and areas were microdissected from one or both sides of each hypothalamus. NPY-IR was detectable in the acid extracts of tissue samples prepared from all the hypothalamic regions studied, with the highest concentrations being found in the infundibular nucleus (325 +/- 53 fmol/mg wet weight of tissue) and the ventromedial nucleus (217 +/- 22 fmol/mg). For the 11 subjects where both sides of the hypothalamus were dissected, values obtained for the areas in one half showed a good degree of symmetry with the corresponding areas on the contralateral side. The infundibular nucleus exhibited the greatest range of values (72-1,137 fmol/mg). Interestingly, variations in other parts of the hypothalamus were observed to parallel those of this nucleus. Expressed as correlation coefficients (r), levels in the infundibular nucleus appeared to be most closely related to those of the ventromedial nucleus (VM; r = 0.89) and paraventricular nucleus (PV; r = 0.84). In addition, retrospective analysis of the clinical histories showed that all patients with very high NPY levels in the infundibular nucleus (621.0 +/- 107.7 fmol/mg; n = 8) had suffered from respiratory failure or severe dyspnea of at least 10 days duration prior to death. The remaining patients (166.7 +/- 17.1 fmol/mg; n = 11) had either died 48 h from the onset of cardiorespiratory difficulties or of unrelated causes.(ABSTRACT TRUNCATED AT 250 WORDS)

Corticotropin releasing factor activity of CRF 41 in normal man is potentiated by angiotensin II and vasopressin but not by desmopressin.

Multiple hypothalamic factors seem to influence ACTH release. In vitro and/or in vivo animal models have shown that angiotensin II, vasopressin and some of its analogs are ACTH secretagogues capable of potentiating the corticotropin releasing activity of CRF41. Since these effects are controversial in man, we investigated in 3 groups of volunteers the corticotropin releasing activity of a 2h-infusion of angiotensin II (7 ng/kg/min), vasopressin (1 ng/kg/min) and desmopressin (1 ng/kg/min) given alone or in combination with a bolus injection of 100 micrograms CRF41 by measuring plasma concentrations of ACTH, cortisol, dehydroepiandrosterone and delta 4-androstenedione. Given alone angiotensin II and desmopressin had no significant effect in contrast to vasopressin which increased significantly the ACTH and steroid levels. Angiotensin II and vasopressin were both able to potentiate the corticotropin releasing activity of CRF41, whereas desmopressin was unable to produce such a potentiation. These results suggest that in man vasopressin and angiotensin II may well regulate the responsiveness of the pituitary-adrenal axis in various physiological or pathophysiological situations.

Angiotensin II Potentiates Corticotropin-Releasing Activity of CRF41 in Rat Anterior Pituitary Cells: Mechanism of Action

In this work the ability of angiotensin II (AII) to potentiate the corticotropin-releasing activity of ovine CRF41 (CRF) and the intracellular mechanism responsible for this effect are described. In perfused rat anterior pituitary cells, AII (10(-8)M) was found to potentiate the corticotropin-releasing activity of CRF producing a parallel shift of the dose-response curve. Similar results for ACTH release were observed in monolayer cell cultures. In this system, the concentration of cAMP was measured and was shown to be increased in the presence of CRF with a maximal value (2.5-fold greater than control) after 5-10 min incubation. On the other hand, AII at a dose inducing ACTH release (10(-7)M), had no effect on basal cAMP concentration, but when given simultaneously with CRF, potentiated the CRF-induced cAMP production (1.9-fold greater than CRF value). These results indicate that AII potentiates the corticotropin-releasing activity of CRF and that this effect is preceded by a similar increase in the CRF-induced cAMP production.

Corticotropin-Releasing Activity of the Renin-Angiotensin System Peptides in Rat and in Man

In this study we investigated in the rat the binding and corticotropin-releasing factor (CRF) activity of various constituents of the renin-angiotensin system and the possible angiotensin II receptor changes following procedures known to alter plasma renin activity. We investigated also the CRF activity of angiotensin II in vitro and in vivo in humans. The CRF activity of peptides was studied by their ability to stimulate ACTH release from pituitary cells. Deleting amino acids from the N-terminus of angiotensin II resulted in decreased CRF activity; while the ED50 for angiotensin II was 2 nM, it increased to about 10 nM for the (2-8)-heptapeptide. Angiotensin I had a weak CRF activity, whereas the substrate angiotensinogen had no stimulatory effect even at a concentration of 100 nM. There was a strong correlation between the activation and binding properties of all peptides tested. Dietary salt load or depletion as well as dexamethasone treatment did not affect the number nor the affinity of pituitary angiotensin II receptors. Angiotensin II had a CRF activity on human pituitary cells in vitro. However, peripherally injected agiotensin II at a pressive dose of 7 ng/kg/min did not produce any ACTH release in normal male volunteers. These data suggest that angiotensin II may play a modulatory role in the physiological regulation of ACTH secretion, but this role might be attributed to the endogenous brain angiotensin II as it is not closely dependent on the angiotensin II plasma levels.

Anatomical localization of corticotropin-releasing activity in the human brain

Corticotropin-releasing activity (CRa) and arginine-vasopressin (AVP) content were measured in seven human hypothalami. The hypothalami were obtained from routine autopsy of patients suffering from no obvious neuroendocrinological abnormality. Twelve distinct hypothalamic areas were dissected in the frozen state and extracted in aqueous solution. CRa was measured by a bioassay measuring the aCTH released by rat pituitary cells in vitro, and vasopressin by direct radioimmunoassay. CRa was detectable in almost every area with the highest values in the supraoptic, paraventricular and infundibular (arcuate) areas. Vasopressin concentrations were maximum in the supraoptic nucleus, followed by the paraventricular and infundibular nuclei. We conclude that: hypothalami obtained from routine autopsy at a general hospital can be used for consistent CRa and vasopressin assay. Vasopressin and CRa are similarly distributed in man and in the rat. In both species, high CRa, which is not explained by AVP, is found in the paraventricular nucleus. The infundibular (arcuate) nucleus seems to display non AVP-dependent CRa much greater in the human than in the rat.

Anatomical Localization of Corticotropin‐Releasing Factor and Arginine Vasopressin in the Human Hypothalamus; the Effect of Corticosteroids on their Concentrations in Human and Rat Hypothalami

In this study, we have determined the distribution of corticotropin‐releasing factor and vasopressin in the human hypothalamus, and investigated the effect of glucocorticoid administration on the concentrations of both peptides. Corticotropin‐releasing factor and vasopressin were measured by a two‐site immunoradiometric assay and/or radioimmunoassay. The presence of both peptides was studied in extracts of eleven areas of the human hypothalamus as well as in the pituitary stalk from autopsied patients who had been free of chronic steroid administration (n = 14) or had received Corticosteroids (n = 5). Unlike vasopressin, corticotropin‐releasing factor was detected in all extracts: the highest concentration was found in the pituitary stalk, whilst the lowest detectable amounts occurred in the supraoptic and lateral areas and in the mammillary bodies. This pattern of distribution is similar to that reported for the rat hypothalamus. The excellent correlation (R = 0.994) between corticotropin‐releasing factor data obtained by immunoradiometric assay and by radioimmunoassay renders the presence of a corticotropin‐releasing factor precursor molecule in the extracts highly unlikely. In the human brain extracts, glucocorticoid treatment affected neither the content, nor the distribution of corticotropin‐releasing factor and vasopressin. In the rats, dexamethasone administration produced a 50% decrease in the vasopressin content (P < 0.05) of the basomedial and dorsal parts of the hypothalamus and had no effect on the corticotropin‐releasing factor content of these areas. These results show that the distribution of corticotropin‐releasing factor is similar in both human and rat hypothalami. The rat data suggest that negative feedback effects of glucocorticoids involve changes in hypothalamic vasopressin content.