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Gary J Schwartz

Publications and source records attributed to Gary J Schwartz.

18 recordsLinked to original sources
PubMed2025

A consensus guide to preclinical indirect calorimetry experiments.

Understanding the complex factors influencing mammalian metabolism and body weight homeostasis is a long-standing challenge requiring knowledge of energy intake, absorption and expenditure. Using measurements of respiratory gas exchange, indirect calorimetry can provide non-invasive estimates of whole-body energy expenditure. However, inconsistent measurement units and flawed data normalization methods have slowed progress in this field. This guide aims to establish consensus standards to unify indirect calorimetry experiments and their analysis for more consistent, meaningful and reproducible results. By establishing community-driven standards, we hope to facilitate data comparison across research datasets. This advance will allow the creation of an in-depth, machine-readable data repository built on shared standards. This overdue initiative stands to markedly improve the accuracy and depth of efforts to interrogate mammalian metabolism. Data sharing according to established best practices will also accelerate the translation of basic findings into clinical applications for metabolic diseases afflicting global populations.

Calorimetry, Indirect↗
PubMed2006

Integrative capacity of the caudal brainstem in the control of food intake.

The caudal brainstem nucleus of the solitary tract (NTS) is the initial central nervous system (CNS) terminus for a variety of gastrointestinal mechanical, nutrient chemical and gut peptide signals that limit the amount of food consumed during a meal. It receives neuroanatomical projections from gut vagal and non-vagal visceral afferents that mediate the CNS representation of these meal-stimulated gut feedback signals, and is reciprocally connected to a range of hypothalamic and limbic system sites that play significant roles in the neural processing of meal-related stimuli and in determining food consumption. Neurons in the NTS also contains elements of leptinergic and melanocortinergic signalling systems, presenting the possibility that the brainstem actions of these neuropeptides affect both the NTS processing of meal-stimulated gut afferent neural activity and its behavioural potency. Taken together, these features suggest that the NTS is ideally situated to integrate central and peripheral signals that determine meal size. This manuscript will review recent support from molecular genetic, neurophysiological and immunocytochemical studies that begin to identify and characterize the types of integrative functions performed within the NTS, and highlight the extent to which they are consistent with a causal role for NTS integration of peripheral gut and central neuropeptide signals important in the control of food intake.

Animals↗
PubMed2006

Dirty dealing: hepatic vagal afferents reshuffle fat distribution.

To evaluate the role of hepatic peroxisome-proliferator-activated receptor (PPAR) gamma 2 in the control of energy balance, Uno and colleagues examined the metabolic effects of overexpression of PPAR gamma 2 selectively in mouse and rat liver. Mice demonstrated a surprising degree of hepatic steatosis accompanied by significant reductions in peripheral adiposity. This crosstalk between liver and adipose tissue appears to be mediated by both the sensory component of the hepatic vagus nerve and sympathetic efferents. These data suggest a novel hepatic-adipose neuraxis that regulates the distribution of stored fat.

Adipose Tissue↗
PubMed2005

Gustatory neural responses in the medial orbitofrontal cortex of the old world monkey.

The primary taste cortex has widespread and occasionally dense projections to the orbitofrontal cortex (OFC) in the macaque. Nonetheless, electrophysiological studies have revealed that only 2-8% of the cells in the OFC are activated by taste stimuli on the tongue. We describe an area centered in Brodmann's area 13m of the medial OFC (mOFC) where taste neurons are more concentrated. It consists of a 12 mm2 core, where gustatory neurons constituted 20% of the population, and a 1 mm perimeter in which 8% of the cells responded to taste. Data were collected from three awake cynomolgus monkeys (Macaca fascicularis) prepared for chronic recording. Single neurons were isolated with epoxylite-coated tungsten microelectrodes and tested for responsiveness to 1.0 m glucose, 0.3 m NaCl, 0.03 m HCl, and 0.001 m QHCl. These stimuli elicited responses that were 96% excitatory and ranged from 5.2 to 5.9 spikes/s. Cells were broadly tuned (H = 0.79), similar to those in the anterior insula (H = 0.70), and decidedly unlike the narrowly tuned taste neurons in the caudolateral OFC (clOFC; H = 0.39). Whereas 82% of the taste cells in the clOFC respond to glucose, in the mOFC, HCl-responsive (56%), glucose-responsive (50%), NaCl-responsive (43%), and QHCl-responsive (40%) cells were almost evenly represented. The mOFC taste area appears to comprise a major gustatory relay that lies anatomically and functionally between the anterior insula and the clOFC.

Animals↗
PubMed2005

Hypothalamic K(ATP) channels control hepatic glucose production.

Obesity is the driving force behind the worldwide increase in the prevalence of type 2 diabetes mellitus. Hyperglycaemia is a hallmark of diabetes and is largely due to increased hepatic gluconeogenesis. The medial hypothalamus is a major integrator of nutritional and hormonal signals, which play pivotal roles not only in the regulation of energy balance but also in the modulation of liver glucose output. Bidirectional changes in hypothalamic insulin signalling therefore result in parallel changes in both energy balance and glucose metabolism. Here we show that activation of ATP-sensitive potassium (K(ATP)) channels in the mediobasal hypothalamus is sufficient to lower blood glucose levels through inhibition of hepatic gluconeogenesis. Finally, the infusion of a K(ATP) blocker within the mediobasal hypothalamus, or the surgical resection of the hepatic branch of the vagus nerve, negates the effects of central insulin and halves the effects of systemic insulin on hepatic glucose production. Consistent with these results, mice lacking the SUR1 subunit of the K(ATP) channel are resistant to the inhibitory action of insulin on gluconeogenesis. These findings suggest that activation of hypothalamic K(ATP) channels normally restrains hepatic gluconeogenesis, and that any alteration within this central nervous system/liver circuit can contribute to diabetic hyperglycaemia.

ATP-Binding Cassette Transporters↗
PubMed2005

Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis.

Increased glucose production is a hallmark of type 2 diabetes and alterations in lipid metabolism have a causative role in its pathophysiology. Here we postulate that physiological increments in plasma fatty acids can be sensed within the hypothalamus and that this sensing is required to balance their direct stimulatory action on hepatic gluconeogenesis. In the presence of physiologically-relevant increases in the levels of plasma fatty acids, negating their central action on hepatic glucose fluxes through (i) inhibition of the hypothalamic esterification of fatty acids, (ii) genetic deletion (Sur1-deficient mice) of hypothalamic K(ATP) channels or pharmacological blockade (K(ATP) blocker) of their activation by fatty acids, or (iii) surgical resection of the hepatic branch of the vagus nerve led to a marked increase in liver glucose production. These findings indicate that a physiological elevation in circulating lipids can be sensed within the hypothalamus and that a defect in hypothalamic lipid sensing disrupts glucose homeostasis.

Animals↗
PubMed2005

A brain-liver circuit regulates glucose homeostasis.

Increased glucose production (GP) is the major determinant of fasting hyperglycemia in diabetes mellitus. Previous studies suggested that lipid metabolism within specific hypothalamic nuclei is a biochemical sensor for nutrient availability that exerts negative feedback on GP. Here we show that central inhibition of fat oxidation leads to selective activation of brainstem neurons within the nucleus of the solitary tract and the dorsal motor nucleus of the vagus and markedly decreases liver gluconeogenesis, expression of gluconeogenic enzymes, and GP. These effects require central activation of ATP-dependent potassium channels (K(ATP)) and descending fibers within the hepatic branch of the vagus nerve. Thus, hypothalamic lipid sensing potently modulates glucose metabolism via neural circuitry that requires the activation of K(ATP) and selective brainstem neurons and intact vagal input to the liver. This crosstalk between brain and liver couples central nutrient sensing to peripheral nutrient production and its disruption may lead to hyperglycemia.

Adenosine Triphosphate↗
PubMed2005

Hypothalamic sensing of fatty acids.

Selective regions of the brain, including the hypothalamus, are capable of gathering information on the body's nutritional status in order to implement appropriate behavioral and metabolic responses to changes in fuel availability. This review focuses on direct metabolic signaling within the hypothalamus. There is growing evidence supporting the idea that fatty acid metabolism within discrete hypothalamic regions can function as a sensor for nutrient availability that can integrate multiple nutritional and hormonal signals.

Acyl Coenzyme A↗
PubMed2004

Sensory neurobiological analysis of neuropeptide modulation of meal size.

Gerry Smith's emphasis on the meal as the functional unit of ingestion spurred experiments designed to (1) identify oral and postoral stimuli that affect meal size, and (2) identify peripheral and central neural mechanisms involved in the processing of sensory signals generated by these stimuli. His observations that gut-brain peptides can limit meal size were important in formulating the idea that neuropeptides involved in the control of food intake modulate the peripheral and central neural processing of meal-stimulated sensory signals. This focus on meal size continues to foster the development of hypotheses and the design of experiments that characterize the sites and modes of action of feeding modulatory neuropeptides. These investigations have focused attention on the gut-brain neuraxis as a critical sensory pathway in the control of ingestive behavior, and have revealed important integrative properties of peripheral and central neurons along this axis. The neuromodulatory function of peptides that alter food intake is supported by their ability to recruit the activation of neurons at multiple central nodes of the gut-brain axis and to affect the neural processing and behavioral potency of meal-related gastrointestinal signals important in the negative feedback control of meal size. This sensory neurobiological perspective may also be applied to determine whether feeding modulatory neuropeptides affect the neural and behavioral potency of oral positive feedback signals that promote ingestion.

Adrenocorticotropic Hormone↗
PubMed2004

Biology of eating behavior in obesity.

Understanding normal and dysfunctional energy regulation and body weight regulation requires neural evaluation of the signals involved in the control of food intake within a meal, as well as signals related to the availability of stored fuels. Work from our laboratory has focused on peripheral and central nervous system studies of behavior and physiology designed to improve our understanding of the role of gut-brain communication in the control of food intake and energy homeostasis. Gastrointestinal administration of nutrients reduces subsequent meal size, suggesting a potent role for peripheral nutrient sensing in the negative feedback control of ingestion. Vagal afferent nerves supply gastrointestinal sites stimulated during food intake, and these nerves are responsive to mechanical and nutrient chemical properties of ingested food. In addition, the presence of nutrients in these gastrointestinal sites stimulates the release of peptides that affect energy intake. These gut peptides also modulate the activity of peripheral gastrointestinal sensory nerves in ways that may contribute to their effects on food intake. In the central nervous system, adiposity hormones and their downstream mediators have been shown to work at both hindbrain and forebrain sites to affect food intake and metabolism. Importantly, recent data has shown that adiposity hormones acting in the brain increase the behavioral and neural potency of feeding inhibitory gastrointestinal stimuli. These data support the suggestion that insensitivity to adiposity hormones in obesity may be characterized by alterations in their ability to modulate the neural processing of food signals important in determining how much food is consumed during a meal.

Brain↗
PubMed2003

Selective effects of vagal deafferentation and celiac-superior mesenteric ganglionectomy on the reinforcing and satiating action of intestinal nutrients.

The role of vagal afferents and splanchnic fibers in nutrient-induced flavor conditioning and feeding suppression was determined. Male rats were fitted with intraduodenal (ID) catheters and given subdiaphragmatic vagal deafferentation (SDA), celiac-superior mesenteric ganglionectomy (CGX), combined (COM) treatments, or sham surgery. In separate conditioning trials, they were trained to drink (30 min/day) flavored saccharin solutions paired with concurrent ID infusions of 8% maltodextrin or water and 3.55% corn oil or water. Experiment 1 revealed that SDA and sham rats showed equal preferences for the nutrient-paired flavors over the water-paired flavors. In contrast, SDA rats, unlike sham rats, failed to suppress their intake of a palatable fluid when infused intraduodenally with maltodextrin or corn oil. Experiment 2 revealed that CGX, COM and sham rats all developed preferences for the maltodextrin-paired flavor, although CGX alone or COM attenuated the conditioned preference. CGX and COM treatments also attenuated or blocked the feeding inhibitory actions of ID nutrient infusions. These findings along with prior data indicate that gut vagal afferents and splanchnic nerves are not essential for flavor-nutrient preference conditioning, whereas both vagal afferents and splanchnic nerves are implicated in carbohydrate- and fat-induced satiation.

Afferent Pathways↗
PubMed2003

Enterostatin inhibition of dietary fat intake is dependent on CCK-A receptors.

Enterostatin, a pentapeptide released from the exocrine pancreas and gastrointestinal tract, selectively inhibits fat intake through activation of an afferent vagal signaling pathway. This study investigated if the effects of enterostatin were mediated through a CCK-dependent pathway. The series of in vivo and in vitro experiments included studies of 1) the feeding effect of peripheral enterostatin on Otsuka Long Evans Tokushima Fatty (OLETF) rats lacking CCK-A receptors, 2) the effect of CCK-8S on the intake of a two-choice high-fat (HF)/low-fat (LF) diet, 3) the effects of peripheral or central injection of the CCK-A receptor antagonist lorglumide on the feeding inhibition induced by either central or peripheral enterostatin, and 4) the ability of enterostatin to displace CCK binding in a 3T3 cell line expressing CCK-A receptor gene and in rat brain sections. The results showed that OLTEF rats did not respond to enterostatin (300 microg/kg ip) in contrast to the 23% reduction in intake of HF diet in Long Evans Tokushima Otsuka (LETO) control rats. CCK (1 microg/kg ip) decreased the intake of the HF diet in a two-choice diet regime with a compensatory increase in intake of the LF diet. Peripheral injection of lorglumide (300 microg/kg) blocked the feeding inhibition induced by either near-celiac arterial or intracerebroventricular enterostatin, whereas intracerebroventricular lorglumide (5 nmol icv) only blocked the response to intracerebroventricular enterostatin but not to arterial enterostatin. Enterostatin did not bind on CCK-A receptors because neither enterostatin nor its analogs VPDPR and beta-casomorphin displaced [3H]L-364,718 from CCK-A receptors expressed in 3T3 cells or the binding of 125I-CCK-8S from rat brain sections. The data suggest that both the peripheral and central responses to enterostatin are mediated through or dependent on peripheral and central CCK-A receptors.

3T3 Cells↗
PubMed2002

Responsivity to NPY and melanocortins in obese OLETF rats lacking CCK-A receptors.

Otsuka Long-Evans Tokushima Fatty (OLETF) rat lacking CCK-A receptors are hyperphagic and obese. Previous work has demonstrated alterations in neuropeptide Y (NPY) and proopiomelanocortin (POMC) mRNA expression in ad libitum fed OLETF rats compared to lean Long-Evans Tokushima Otsuka (LETO) controls. In order to determine whether alterations in sensitivity to central peptides involved in overall feeding control may contribute to the hyperphagia and obesity in OLETF rats, we assessed OLETF and LETO rats feeding responses to lateral ventricular infusions of NPY (1 and 3.2 nmol), the melanocortin 3/4 agonist MTII (0.1 and 0.32 nmol) and the melanocortin receptor antagonist SHU-9119 (0.25 and 0.5 nmol). At a 3-h time point, NPY increased food intake in both OLETF and LETO rats. OLETF rats were more sensitive, having significant increases at both NPY doses and a greater increase at the higher dose. The melanocortin agonist MTII decreased intake in both LETO and OLETF rats. At the 20-h time point, the magnitude of suppression was greater in OLETF rats. SHU-9119 increased food intake in both groups. OLETF rats were more sensitive with larger relative increase and longer-lasting effects at the lower dose. These results are consistent with demonstrated alterations in neuropeptide gene expression in OLETF rats and indicate that alterations in responsivity to NPY and melanocortin signaling are unlikely to contribute to their hyperphagia and obesity.

Animals↗
PubMed2002

Central melanocortin receptor agonist reduces spontaneous and scheduled meal size but does not augment duodenal preload-induced feeding inhibition.

Central melanocortin (MC) receptor agonists inhibit food intake and may be downstream mediators of the effects of central leptin, which (1) reduces food intake by selectively decreasing meal size and (2) augments the feeding-inhibitory effects of gastrointestinal food stimuli. Central administration of the MC-3/4 receptor (MC-3/4R) agonist, MTII, inhibits feeding in rats, but its effects on meal pattern and potential interactions with gastrointestinal controls of food intake remain unclear. We examined meal patterns and intake in male Sprague-Dawley rats following central intracerebroventricular administration of MTII (0.01-1.0 nmol) in two situations: (1) during daytime 60-min scheduled access to liquid glucose (12.5%) in combination with a duodenal preload of 12.5% glucose or physiological saline (4.4 ml/10 min), and (2) during subsequent overnight access to 45 mg of solid chow pellets. Both duodenal glucose preloads and MTII reduced subsequent glucose intake. However, no dose of MTII augmented the reductions in food intake produced by duodenal glucose alone. During overnight access to pelleted chow, the 0.1- and 1.0-nmol doses of MTII reduced food intake, meal size, meal duration, and body weight, and increased the satiety ratio (duration of intermeal interval/preceding meal size) but did not change meal frequency. The present data (1) demonstrate that MTII, like leptin, reduces food intake by a selective reduction in meal size and not meal frequency, and (2) suggest that MTII increases the feeding-inhibitory potency of negative feedback signals critical to the control of meal size during spontaneous chow access, but not scheduled access to palatable liquid nutrient solutions.

Animals↗
PubMed2002

Neural-immune gut-brain communication in the anorexia of disease.

Peripheral administration of toxic bacterial products and cytokines have been used to model the immunological, physiological, and behavioral responses to infection, including the anorexia of disease. The vagus nerve is the major neuroanatomic linkage between gut sites exposed to peripheral endotoxins and cytokines and the central nervous system regions that mediate the control of food intake, and thus has been a major research focus of the neurobiological approach to understanding cytokine-induced anorexia. Molecular biological and neurophysiologic evidence demonstrates that peripheral anorectic doses of cytokines and endotoxins elicit significant increases in neural activation at multiple peripheral and central levels of the gut-brain axis and in some cases may modify the neural processing of meal-related gastrointestinal signals that contribute to the negative feedback control of ingestion. However, behavioral studies of the anorectic effects of peripheral cytokines and endotoxins have shown that neither vagal nor splanchnic visceral afferent fibers supplying the gut are necessary for the reduction of food intake in these models. These data do not rule out 1) the potential contribution of supradiaphragmatic vagal afferents or 2) a modulatory role for immune-stimulated gut vagal afferent signals in the expression of cytokine and endotoxin-induced anorexia in the intact organism.

Acute-Phase Reaction↗
PubMed2002

Leptin and neuropeptide y have opposing modulatory effects on nucleus of the solitary tract neurophysiological responses to gastric loads: implications for the control of food intake.

Leptin is an adiposity hormone that modulates the activity of multiple hypothalamic signaling pathways involved in the control of food intake. The present experiments were designed to evaluate whether central administration of leptin or one of its downstream mediators, neuropeptide Y (NPY), could affect food intake by modulating the brain stem neurophysiological response to ascending meal-related feedback signals in the nucleus of the solitary tract (NTS) in anesthetized male Long-Evans rats. NTS neurons at the rostrocaudal level of the area postrema were dose-dependently activated by gastric loads ranging from 2-10 ml, and leptin and NPY had opposite modulatory effects on this load volume/activity relationship: leptin significantly increased NTS responses to gastric loads, whereas NPY reduced the potency and efficacy with which gastric loads activated NTS neurons. These effects were probably not mediated by peripheral effects of centrally administered peptides or by the gastrokinetic effects of central NPY or leptin, because the dose-response relationship between gastric load volume and neurophysiological firing rate was unchanged in gastric load-sensitive vagal afferent fibers. These data suggest a mechanistic framework for considering how feeding behavior occurring in meals is altered by challenges to energy homeostasis, such as fasting and overfeeding.

Animals↗