Search PubMed⌕ Search

Biomedical subjects

M W Schwartz

Publications and source records attributed to M W Schwartz.

At least 19 recordsLinked to original sources
PubMed1996

Identification of targets of leptin action in rat hypothalamus.

The hypothesis that leptin (OB protein) acts in the hypothalamus to reduce food intake and body weight is based primarily on evidence from leptin-deficient, ob/ob mice. To investigate whether leptin exerts similar effects in normal animals, we administered leptin intracerebroventricularly (icv) to Long-Evans rats. Leptin administration (3.5 microg icv) at the onset of nocturnal feeding reduced food intake by 50% at 1 h and by 42% at 4 h, as compared with vehicle-treated controls (both P < 0.05). To investigate the basis for this effect, we used in situ hybridization (ISH) to determine whether leptin alters expression of hypothalamic neuropeptides involved in energy homeostasis. Two injections of leptin (3.5 microg icv) during a 40 h fast significantly decreased levels of mRNA for neuropeptide Y (NPY, which stimulates food intake) in the arcuate nucleus (-24%) and increased levels of mRNA for corticotrophin releasing hormone (CRH, an inhibitor of food intake) in the paraventricular nucleus (by 38%) (both P < 0.05 vs. vehicle-treated controls). To investigate the anatomic basis for these effects, we measured leptin receptor gene expression in rat brain by ISH using a probe complementary to mRNA for all leptin receptor splice variants. Leptin receptor mRNA was densely concentrated in the arcuate nucleus, with lower levels present in the ventromedial and dorsomedial hypothalamic nuclei and other brain areas involved in energy balance. These findings suggest that leptin action in rat hypothalamus involves altered expression of key neuropeptide genes, and implicate leptin in the hypothalamic response to fasting.

Animals↗
PubMed1996

The evaluation of insulin as a metabolic signal influencing behavior via the brain.

The intent of this paper is to evaluate decreases of food intake and body weight that occur when a peptide is administered to an animal. Using the pancreatic hormone insulin as an example, the case is made that endogenous insulin is normally secreted in response to circulating nutrients as well as in proportion to the degree of adiposity. Hence, its levels in the blood are a reliable indicator of adiposity. A further case is then made demonstrating that insulin is transported through the blood-brain barrier into the brain, where it gains access to neurons containing specific insulin receptors that are important in the control of feeding and metabolism. Finally, experimentally-induced changes of insulin in the brain cause predictable changes of food intake and body weight. Given these observations, the question is then asked: since endogenous insulin, acting within the brain, appears to decrease food intake, can a decrease of food intake caused by exogenous insulin administered into the same area of the brain be ascribed to the same, naturally-occurring response system, or should it be attributed to malaise or a non-specific depression of behavior? Arguments are presented supporting the former position that exogenous insulin, when administered in small quantities directly into the brain, taps into the natural caloric/metabolic system and hence influences food intake and body weight.

Animals↗
PubMed1996

Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans.

The adipocyte hormone, leptin (OB protein), is proposed to be an "adiposity signal" that acts in the brain to lower food intake and adiposity. As plasma leptin levels are elevated in most overweight individuals, obesity may be associated with leptin resistance. To investigate the mechanisms underlying brain leptin uptake and to determine whether reduced uptake may contribute to leptin resistance, we measured immunoreactive leptin levels in plasma and cerebrospinal fluid (CSF) of 53 human subjects. Leptin concentrations in CSF were strongly correlated to the plasma level in a nonlinear manner (r = 0.92; p = 0.0001). Like levels in plasma, CSF leptin levels were correlated to body mass index (r = 0.43; p = 0.001), demonstrating that plasma leptin enters human cerebrospinal fluid in proportion to body adiposity. However, the efficiency of this uptake (measured as the CSF:plasma leptin ratio) was lower among those in the highest as compared with the lowest plasma leptin quintile (5.4-fold difference). We hypothesize that a saturable mechanism mediates CSF leptin transport, and that reduced efficiency of brain leptin delivery among obese individuals with high plasma leptin levels results in apparent leptin resistance.

Adult↗
PubMed1996

Behavioral, endocrine, and hypothalamic responses to involuntary overfeeding.

The suppression of food intake after a period of forced overfeeding is potent and long lasting, yet little is known of the underlying mechanisms for this regulatory response. Rats were overfed via a surgically implanted gastrostomy tube. During overfeeding, plasma insulin and corticotropin-releasing hormone (CRH) mRNA in the paraventricular nucleus of the hypothalamus were elevated compared with controls and with overfed rats allowed 3 days to recover from the overfeeding regimen such that body weight returned to the level of controls. In contrast, rats that were not overfed but were pair-fed to the low spontaneous food intake of previously overfed rats lost weight and had significantly reduced plasma insulin and elevated mRNA for neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus. The results indicate that overfeeding produces an activation of hypothalamic CRH system that may contribute to the hypophagia that accompanies involuntary overfeeding. Furthermore, the hypothalamic NPY response to food restriction is not tied to low food intake per se, but rather to negative energy balance.

Animals↗
PubMed1996

Insulin transport from plasma into the central nervous system is inhibited by dexamethasone in dogs.

We have previously shown that transport of plasma insulin into the central nervous system (CNS) is mediated by a saturable mechanism consistent with insulin binding to blood-brain barrier insulin receptors and subsequent transcytosis through microvessel endothelial cells. Since glucocorticoids antagonize insulin receptor-mediated actions both peripherally and in the CNS, we hypothesized that glucocorticoids also impair CNS insulin transport. Nine dogs were studied both in the control condition and after 7 days of high-dose oral dexamethasone (DEX) administration (12 mg/day) by obtaining plasma and cerebrospinal fluid (CSF) samples over 8 h for determination of immunoreactive insulin levels during a 90-min euglycemic intravenous insulin infusion (plasma insulin approximately 700 pmol/l). From these data, the kinetics of CNS insulin uptake and removal were determined using a mathematical model with three components (plasma-->intermediate compartment, hypothesized to be brain interstitial fluid-->CSF). DEX increased basal insulin levels 75% from 24 +/- 6 to 42 +/- 30 pmol/l (P < 0.005) and slightly increased basal glucose levels from 5.0 +/- 0.7 to 5.3 +/- 1.0 mmol/l (P < 0.05). DEX also lowered the model rate constant characterizing CNS insulin transport by 49% from 5.3 x 10(-6) +/- 4.0 x 10(-6) to 2.7 x 10(-6) +/- 1.2 x 10(-6) min-2 (P < or = 0.001). As glucocorticoids are known to reduce CSF turnover, we also hypothesized that the model rate constant associated with CSF insulin removal would be decreased by DEX. As expected, the model rate constant for CSF insulin removal decreased 47% from 0.038 +/- 0.013 to 0.020 +/- 0.088 min-1 (P < or = 0.0005) during DEX treatment. We conclude that DEX impairs CNS insulin transport. This finding supports our hypothesis that insulin receptors participate in the CNS insulin transport process and that this process may be subject to regulation. Moreover, since increasing brain insulin transport reduces food intake and body adiposity, this observation provides a potential mechanism by which glucocorticoid excess leads to increased body adiposity.

Animals↗
PubMed1996

Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice.

Correction of the obese state induced by genetic leptin deficiency reduces elevated levels of both blood glucose and hypothalamic neuropeptide Y (NPY) mRNA in ob/ob mice. To determine whether these responses are due to a specific action of leptin or to the reversal of the obese state, we investigated the specificity of the effect of systemic leptin administration to ob/ob mice (n = 8) on levels of plasma glucose and insulin and on hypothalamic expression of NPY mRNA. Saline-treated controls were either fed ad libitum (n = 8) or pair-fed to the intake of the leptin-treated group (n = 8) to control for changes of food intake induced by leptin. The specificity of the effect of leptin was further assessed by 1) measuring NPY gene expression in db/db mice (n = 6) that are resistant to leptin, 2) measuring NPY gene expression in brain areas outside the hypothalamus, and 3) measuring the effect of leptin administration on hypothalamic expression of corticotropin-releasing hormone (CRH) mRNA. Five daily intraperitoneal injections of recombinant mouse leptin (150 micrograms) in ob/ob mice lowered food intake by 56% (P < 0.05), body weight by 4.1% (P < 0.05), and levels of NPY mRNA in the hypothalamic arcuate nucleus by 42.3% (P < 0.05) as compared with saline-treated controls. Pair-feeding of ob/ob mice to the intake of leptin-treated animals produced equivalent weight loss, but did not alter expression of NPY mRNA in the arcuate nucleus. Leptin administration was also without effect on food intake, body weight, or NPY mRNA levels in the arcuate nucleus of db/db mice. In ob/ob mice, leptin did not alter NPY mRNA levels in cerebral cortex or hippocampus or the expression of CRH mRNA in the hypothalamic paraventricular nucleus (PVN). Leptin administration to ob/ob mice also markedly reduced serum glucose (8.3 +/- 1.2 vs. 24.5 +/- 3.8 mmol/l; P < 0.01) and insulin levels (7,263 +/- 1,309 vs. 3,150 +/- 780 pmol/l), but was ineffective in db/db mice. Pair-fed mice experienced reductions of glucose and insulin levels that were < 60% of the reduction induced by leptin. The results suggest that in ob/ob mice, systemic administration of leptin inhibits NPY gene overexpression through a specific action in the arcuate nucleus and exerts a hypoglycemic action that is partly independent of its weight-reducing effects. Furthermore, both effects occur before reversal of the obesity syndrome. Defective leptin signaling due to either leptin deficiency (in ob/ob mice) or leptin resistance (in db/db mice) therefore leads directly to hyperglycemia and the overexpression of hypothalamic NPY that is implicated in the pathogenesis of the obesity syndrome.

Animals↗
PubMed1995

Intraventricular insulin and the level of maintained body weight in rats.

To determine whether central insulin administration lowers the level around which body weight is regulated, insulin (6 mU/day) or saline was infused into the third ventricles of four groups of rats. One insulin-infused and one saline-infused group were food-deprived for 3 days and were then returned to an ad lib feeding schedule. The other two groups were maintained on ad lib feeding throughout. Insulin-fused food-deprived rats. In ad lib fed rats, insulin caused a significant reduction of food intake and weight relative to saline-infused controls. When formerly food-deprived rats were returned to ad lib feeding, they gained weight, and this was significantly more pronounced in the saline-infused than the insulin-fused group. The body weights of the two insulin-infused groups converged on a value approximately 9% below the average of the two saline infused groups, with one group increasing its weight and the other decreasing its weight to achieve that weight. These findings suggest that the third-ventricular infusion of insulin does not incapacitate the rats and that they can alter their food intake either upward or downward to attain a new weight. The results are also consistent with the hypothesis that direct administration of insulin into the brain determines the level of weight maintained by the animal.

Animals↗
PubMed1995

New model for the regulation of energy balance and adiposity by the central nervous system.

We describe a new model for adiposity regulation in which two distinct classes of peripheral afferent signals modulate neuronal pathways in the brain that control meal initiation, meal termination, and the autonomic outflow influencing the fate of ingested energy. These brain pathways, termed central-effector pathways for the control of energy balance, respond to 1) short-term, situational-, and meal-related signals that are crucial to the size and timing of individual meals, but that are not components of the system serving to regulate adipose stores, and 2) long-term, adiposity-related signals that participate in the negative feedback control of fat stores. Long-term signals, such as the pancreatic hormone insulin, are secreted into the circulation in proportion to energy balance and adipose mass. These signals enter the brain where they influence central-effector pathways, in part by changing the sensitivity of these pathways to short-term signals. Through this mechanism, the central nervous system response to short-term signals is adjusted in proportion to changes in body adiposity, resulting in compensatory changes in food intake and energy expenditure that collectively favor the long-term stability of fat stores. This model provides a comprehensive framework for experimental design and data interpretation in the study of body adiposity regulation.

Adipose Tissue↗
PubMed1995

Glucocorticoids and insulin: reciprocal signals for energy balance.

Signals that regulate long-term energy balance have been difficult to identify. Increasingly strong evidence indicates that insulin, acting on the central nervous system in part through its effect on neuropeptide Y (NPY), inhibits food intake. We hypothesized that corticosteroids and insulin might serve as interacting, reciprocal signals for energy balance, acting on energy acquisition, in part through their effects on hypothalamic NPY, as well as on energy stores. Because glucocorticoids also stimulate insulin secretion, their role is normally obscured. Glucocorticoids and insulin were clamped in adrenalectomized rats with steroid replacement and streptozotocin-induced diabetes. Glucocorticoids stimulated and insulin inhibited NPY mRNA and food intake. Glucocorticoids inhibited and insulin increased energy gain as determined by the change in body weight. When adrenalectomized diabetic rats were treated, corticosterone stimulated and insulin inhibited food intake, and, respectively, inhibited and increased overall energy gain. More than 50% of the variance was explained by regression analysis of the two hormones on food intake and body weight. Thus glucocorticoids and insulin are major, antagonistic, long-term regulators of energy balance. The effects of corticosterone and insulin on food intake may be mediated, in part, through regulation of hypothalamic NPY synthesis and secretion.

Adrenalectomy↗
PubMed1995

Hypothalamic response to starvation: implications for the study of wasting disorders.

Weight loss is a potent stimulus to food intake in normal individuals. The persistence of anorexia in wasting disorders, therefore, implies a failure of this adaptive feeding response. We describe a model for the normal hypothalamic response to starvation composed of the stimulation of neuronal pathways that promote energy intake and storage coupled with the inhibition of pathways that exert opposing effects. This model provides a framework for investigating disturbances of the normal hypothalamic response to weight loss and suggests a specific mechanism by which cytokines contribute to wasting in acquired immune deficiency syndrome and other cachexic disorders.

Animals↗
PubMed1995

Estradiol inhibits the increase of hypothalamic neuropeptide Y messenger ribonucleic acid expression induced by weight loss in ovariectomized rats.

Anorexia and weight loss produced by estradiol (E2) may involve altered expression of neuropeptide Y (NPY) in the hypothalamus. We tested this hypothesis using ovariectomized (OVX) rats by replacing E2 with SILASTIC brand capsule implants and measuring NPY messenger RNA (mRNA) levels in the arcuate nucleus by in situ hybridization. To equalize the effects of weight loss on NPY mRNA expression, E2 deficient OVX rats were pair-fed (n = 10) for 2 days to an OVX group receiving E2 (n = 12). Compared with the weight gain (P < 0.02) of E2 deficient OVX rats (n = 10), OVX rats replaced with E2 and pair-fed OVX rats both had 12.5% lower food intake and weight (P < 0.05). E2 replacement elevated insulin 52% (P < 0.05) and lowered NPY hybridization 32% (P < 0.05) compared with pair-fed controls. During a 2-day fast, E2 replacement (N = 12) attenuated the elevation of NPY mRNA levels 50% (P < 0.01) compared with E2 deficiency (n = 15). Therefore, when E2 is administered to OVX rats, reduced NPY mRNA expression in the hypothalamus is unlikely to be a primary cause of weight loss, although it may contribute to the maintenance of reduced food intake and body weight.

Animals↗
PubMed1995

Reduced insulin secretion: an independent predictor of body weight gain.

A causal role in the pathogenesis of obesity has been proposed for hyperinsulinemia and insulin resistance in populations with a high prevalence of a "thrifty genotype." An alternative hypothesis is that obesity-induced hyperinsulinemia is an adaptation which, by increasing central nervous system insulin signaling (which suppresses food intake), confers resistance to weight gain. To characterize the relationship between the level of insulin secretion and the risk of weight gain, we examined whether any of three different measures of the level of insulin secretion (the area under the plasma insulin curve during both a meal tolerance test and an oral glucose tolerance test, and the acute insulin secretory response to iv glucose) was predictive of weight gain in a prospective study of 97 Pima Indians (64 males and 33 females) with normal glucose tolerance. During a mean (+/- SD) follow-up period of more than 3 yr (males, 3.58 +/- 1.46 yr; females, 3.02 +/- 1.73 yr), average weight increased 2.1 +/- 3.0%/yr in males and 3.5 +/- 3.6%/yr in females, reflecting a mean annual increase in body fat content of 6.9%/yr in both sexes. Insulin secretion was negatively associated with the rate of weight gain, whether assessed by the insulin response during the meal tolerance test (r = -0.35; P < 0.001), the oral glucose tolerance test (r = -0.30; P = 0.004), or the acute insulin secretory response to iv glucose (r = -0.28; P = 0.002). Moreover, the significance of the relationship between each measure of insulin secretion and weight gain persisted after controlling for differences in age, sex, initial body weight, and insulin sensitivity. Relatively reduced insulin secretion, therefore, is a significant and independent predictor of the tendency to gain weight and adiposity in Pima Indians. The presence of relative insulin resistance also conferred an independent reduction in the risk of weight gain in some regression analyses. We conclude that insulin resistance and hyperinsulinemia are unlikely to play a causal role in the development of obesity, and that relatively reduced insulin secretion is a marker of an increased risk of weight gain in this population. These conclusions support the hypothesis that the level of insulin secretion plays an important role in long term body weight regulation.

Adipose Tissue↗
PubMed1995

Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression.

To test the hypothesis that diabetic hyperphagia results from insulin deficiency in the brain, diabetic rats (streptozotocin-induced) were given an intracerebroventricular (ICV) infusion of saline or insulin (at a dose that did not affect plasma glucose levels) for 6 days. Food and water intake were significantly increased in diabetic rats, but only food intake was affected by ICV insulin. Diabetic hyperphagia was reduced 58% by ICV insulin compared with ICV saline (P < 0.05) and was accompanied by a 69% increase in diabetes-induced weight loss (P < 0.05). To evaluate whether central nervous system (CNS) insulin deficiency affects expression of neuropeptides involved in food intake, in situ hybridization was done for neuropeptide Y (NPY), which stimulates feeding, in the hypothalamic arcuate nucleus and for cholecystokinin (CCK) and corticotropin-releasing hormone (CRH), which inhibit feeding, in the hypothalamic paraventricular nucleus. In diabetic rats, NPY mRNA hybridization increased 280% (P < 0.05), an effect reduced 40% by ICV insulin (P < 0.05). CCK mRNA hybridization increased 50% in diabetic rats (P < 0.05), a response reduced slightly by ICV insulin (P < 0.05), whereas CRH mRNA hybridization decreased 33% in diabetic rats (P < 0.05) and was unchanged by ICV insulin. The results demonstrate that CNS infusion of insulin to diabetic rats reduces both hyperphagia and overexpression of hypothalamic NPY mRNA. This observation supports the hypothesis that a deficiency of insulin in the brain is an important cause of diabetic hyperphagia and that increased hypothalamic NPY gene expression contributes to this phenomenon.

Animals↗
PubMed1995

Localization of Na, K-ATPase isoforms in the hypothalamus of the rat.

In situ hybridization histochemistry with synthetic oligonucleotide probes was used to localize mRNAs encoding three isoforms of the catalytic (alpha) subunit and one isoform of the (beta) subunit of the Na, K-ATPase in rat hypothalamus using contact film radioautography. 3H-Ouabain binding to specific anatomical nuclei in the hypothalamus was determined using a quantitative radioautographic technique previously developed in our laboratory. Specific hybridization was found with oligonucleotide probes for mRNA encoding alpha 1, alpha 2, alpha 3, beta 1 isoforms of the Na, K-ATPase. High levels of hybridization signal for alpha 3 and beta 1 were found in ventromedial hypothalamus, supraoptic nucleus, paraventricular nucleus and the anterior hypothalamic area. Very low levels of hybridization for all isoforms were found in the optic chiasm. mRNAs encoding alpha 1 and alpha 2 isoforms were expressed at lower levels than alpha 3. The distribution of alpha 2 was consistent with expression in glial cells. Generally, levels of alpha 1 mRNA were higher in the arcuate nucleus than in other hypothalamic regions and very low levels were found in the anterior hypothalamic area. 3H-Ouabain binding was relatively diffuse, consistent with the localization of the synthesized Na, K-ATPase protein in cellular processes. The number of 3H-ouabain binding sites in the paraventricular nucleus was significantly lower than other hypothalamic nuclei studied. The results suggest that Na, K-ATPase isoforms may be differentially expressed in hypothalamic nuclei.

Animals↗
PubMed1994

Community critical care course: blueprint for success.

For 10 years, a group of 19 California hospitals has supported a community-based critical care educational program for entry-level critical care nurses. Program management is rotated every two years. Two courses are offered quarterly: a 32-hour ECG course and a 96-hour Critical Care Nursing course. The community-based approach is very well received because it provides broad-based critical care educational programs in a very cost-effective manner.

California↗
PubMed1994

Insulin receptor substrate-1 (IRS-1) expression in rat brain.

IRS-1 is phosphorylated on tyrosine residues after insulin stimulation and participates in the early events of signal transduction in peripheral insulin-sensitive tissues. This study determined whether neuronal populations in the rat olfactory bulb and hippocampus (brain regions which have very high concentrations of insulin receptors) also express IRS-1 and contain phosphotyrosine, using in situ hybridization, receptor binding, and immunocytochemistry. IRS-1 mRNA was colocalized with insulin receptor mRNA in neuron cell bodies of hippocampus and olfactory bulb. Similarly, IRS-1 immunoreactivity in hippocampus and olfactory bulb was concentrated in layers that contain synapses of these neurons and have both high insulin binding and phosphotyrosine levels. Thus, IRS-1 and insulin receptors are coexpressed in discrete populations of neurons, suggesting a signal transduction mechanism by which insulin may influence metabolism and gene expression in the brain.

Animals↗