Gregory J Morton

University of Washington Seattle, Seattle, WA, United States

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Publications (62)525.27 Total impact

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    ABSTRACT: Context.Fibroblast growth factor 19 (FGF19) improves glycemic control in diabetic animals and is secreted from the gastrointestinal tract following meals in response to bile acid stimulation.Objective.We sought to understand how ingestion of carbohydrates, protein or lipids affect both FGF19 and bile acid concentrations in human plasma, with the hypothesis that variation in the bile acid response to different macronutrients would predict differences in plasma FGF19 levels.Design.This was a randomized, within-subjects crossover study.Setting.The study was conducted at a University Clinical Research Center.Participants.There were 16 healthy human subjects included in the study.Interventions.Isocaloric, isovolemic beverages composed primarily of carbohydrates, proteins, or lipids were provided to each participant on three separate occasions.Main Outcome Measures.The magnitudes of postprandial rises of plasma FGF19 and total bile acid levels were determined.Results.All beverages induced an initial transient decline of plasma FGF19 levels during the first 60 min following consumption. For FGF19, the ingestion of carbohydrate was associated with the fastest and highest increase of plasma levels, returning to baseline at 5h. By comparison, the protein beverage induced a modest but significant elevation of FGF19 levels that peaked at the end of the 6-h sampling interval, while a lipid beverage was without effect. In contrast, total bile acid levels increased in plasma only in response to a high lipid beverage, demonstrating a marked divergence between the FGF19 and bile acid response to lipid vs. carbohydrate.Conclusions.A bile acid-independent mechanism is implicated in the effect of meals to raise plasma FGF19 concentrations.
    The Journal of clinical endocrinology and metabolism 12/2013; · 6.50 Impact Factor
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    ABSTRACT: Although a prominent role for the brain in glucose homeostasis was proposed by scientists in the nineteenth century, research throughout most of the twentieth century focused on evidence that the function of pancreatic islets is both necessary and sufficient to explain glucose homeostasis, and that diabetes results from defects of insulin secretion, action or both. However, insulin-independent mechanisms, referred to as 'glucose effectiveness', account for roughly 50% of overall glucose disposal, and reduced glucose effectiveness also contributes importantly to diabetes pathogenesis. Although mechanisms underlying glucose effectiveness are poorly understood, growing evidence suggests that the brain can dynamically regulate this process in ways that improve or even normalize glycaemia in rodent models of diabetes. Here we present evidence of a brain-centred glucoregulatory system (BCGS) that can lower blood glucose levels via both insulin-dependent and -independent mechanisms, and propose a model in which complex and highly coordinated interactions between the BCGS and pancreatic islets promote normal glucose homeostasis. Because activation of either regulatory system can compensate for failure of the other, defects in both may be required for diabetes to develop. Consequently, therapies that target the BCGS in addition to conventional approaches based on enhancing insulin effects may have the potential to induce diabetes remission, whereas targeting just one typically does not.
    Nature 11/2013; 503(7474):59-66. · 38.60 Impact Factor
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    ABSTRACT: Leptin, a hormone secreted by adipocytes, plays a crucial role in regulating energy balance. Estrogen, like leptin, reduces food intake and adiposity while increasing energy expenditure in animals and humans of both sexes through its actions on the central nervous system. We reviewed the literature for studies of the effects of exogenously administered estrogen on serum leptin concentrations and adiposity in women. Using PubMed/Medline, we searched for studies of hormone therapy that enrolled healthy postmenopausal women. Studies were further evaluated to determine if leptin and adiposity were monitored both at baseline and throughout a treatment period of at least 2 months. Twenty articles met inclusion criteria. We found no consistent effects of exogenous estrogen on serum leptin concentrations, adiposity, or weight gain. Despite suggestive data from animal studies, the current literature does not provide compelling evidence that estrogen therapy attenuates weight gain, alters circulating leptin levels, or improves leptin action in postmenopausal women.
    Menopause (New York, N.Y.) 10/2013; · 3.08 Impact Factor
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    ABSTRACT: Insulin-independent glucose disposal (referred to as glucose effectiveness [GE]) is crucial for glucose homeostasis and, until recently, was thought to be invariable. However, GE is reduced in type 2 diabetes and markedly decreased in leptin-deficient ob/ob mice. Strategies aimed at increasing GE should therefore be capable of improving glucose tolerance in these animals. The gut-derived hormone FGF19 has previously been shown to exert potent antidiabetic effects in ob/ob mice. In ob/ob mice, we found that systemic FGF19 administration improved glucose tolerance through its action in the brain and that a single, low-dose i.c.v. injection of FGF19 dramatically improved glucose intolerance within 2 hours. Minimal model analysis of glucose and insulin data obtained during a frequently sampled i.v. glucose tolerance test showed that the antidiabetic effect of i.c.v. FGF19 was solely due to increased GE and not to changes of either insulin secretion or insulin sensitivity. The mechanism underlying this effect appears to involve increased metabolism of glucose to lactate. Together, these findings implicate the brain in the antidiabetic action of systemic FGF19 and establish the brain's capacity to rapidly, potently, and selectively increase insulin-independent glucose disposal.
    The Journal of clinical investigation 10/2013; · 15.39 Impact Factor
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    ABSTRACT: The β-defensins are a class of small, cationic proteins first recognized as antimicrobial components of the innate and adaptive immune system. More recently, one of the major β-defensins produced in skin, β-defensin 3, has been discovered to function as a melanocortin receptor ligand in vivo and in vitro, but its biophysical and pharmacological basis of action has been enigmatic. Here, we report functional and biochemical studies focused on human β-defensin 3 (HBD3) and melanocortin receptors 1 and 4. Genetic and pharmacologic studies indicate that HBD3 acts as a neutral melanocortin receptor antagonist capable of blocking the action of either stimulatory agonists such as α-melanocyte stimulating hormone or inhibitory inverse agonists such as Agouti signaling protein (ASIP) and Agouti-related protein (AGRP). A comprehensive structure-function analysis demonstrates that two patches of positively charged residues, located on opposite poles of HBD3 and spatially organized by the compact β-defensin fold, are primarily responsible for high-affinity binding to melanocortin receptors. These findings identify a distinct mode of melanocortin receptor-ligand interactions based primarily on electrostatic complementarity, with implications for designing ligands that target melanocortin and potentially other seven transmembrane receptors.
    Chemistry & biology 06/2013; 20(6):784-95. · 6.52 Impact Factor
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    ABSTRACT: In rodent models of type 1 diabetes, leptin administration into brain ventricles normalizes blood glucose at doses that have no effect when given peripherally. The ventromedial nucleus of the hypothalamus (VMN) is a potential target for leptin's anti-diabetic effects since leptin-sensitive neurons in this brain area are implicated in glucose homeostasis. To test this hypothesis, we injected leptin directly into the bilateral VMN of rats with streptozotocin-induced uncontrolled diabetes mellitus (STZ-DM). This intervention completely normalized both hyperglycemia and the elevated rates of hepatic glucose production (HGP) and plasma glucagon levels, but had no effect on tissue glucose uptake in skeletal muscle or brown adipose tissue as measured using tracer dilution techniques during a basal clamp. To determine if VMN leptin signaling is required for leptin-mediated normalization of diabetic hyperglycemia, we studied mice in which the leptin receptor gene was deleted in VMN steroidogenic factor 1 (SF1) neurons using cre-loxP technology. Our findings indicate leptin action within these neurons is not required for correction of diabetic hyperglycemia by central leptin infusion. We conclude that leptin signaling in the VMN is sufficient to mediate leptin's anti-diabetic action, but may not be necessary for this effect. Leptin action within a distributed neuronal network may mediate its effects on glucose homeostasis.
    Endocrinology 06/2013; · 4.72 Impact Factor
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    ABSTRACT: Recent advances in human brown adipose tissue (BAT) imaging technology have renewed interest in the identification of BAT activators for the treatment of obesity and diabetes. In uncontrolled diabetes (uDM), activation of BAT is implicated in glucose lowering mediated by intracerebroventricular (icv) administration of leptin, which normalizes blood glucose levels in streptozotocin (STZ)-induced diabetic rats. The potent effect of icv leptin to increase BAT glucose uptake in STZ-diabetes is accompanied by the return of reduced plasma thyroxine (T4) levels and BAT uncoupling protein-1 (Ucp1) mRNA levels to non-diabetic controls. We therefore sought to determine whether activation of thyroid hormone receptors is sufficient in and of itself to lower blood glucose levels in STZ-diabetes, and whether this effect involves activation of BAT. We found that although systemic administration of the thyroid hormone (TR)-β selective agonist GC-1 increases energy expenditure and induces further weight loss in STZ-diabetic rats, it neither increased BAT glucose uptake nor attenuated diabetic hyperglycemia. Even when GC-1 was administered in combination with a β3-AR agonist to mimic sympathetic nervous system activation, glucose uptake was not increased in STZ-diabetic rats nor was blood glucose lowered, yet this intervention potently activated BAT. Similar results were observed in animals treated with active thyroid hormone (T3) instead of GC-1. Taken together, our data suggest that neither returning normal plasma thyroid hormone levels nor BAT activation have any impact on diabetic hyperglycemia, and that in BAT, increases of Ucp1 gene expression and glucose uptake are readily dissociated from one another in this setting.
    AJP Endocrinology and Metabolism 02/2013; · 4.51 Impact Factor
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    ABSTRACT: The mediobasal hypothalamus (MBH) plays a central role in the regulation of food intake and energy balance. Although the excitatory neurotransmitter glutamate is implicated in energy balance regulation by the MBH, the hypothesis that feeding elicits local glutamate release remains untested. To test this hypothesis, we employed a glutamate biosensor that measures glutamate concentrations at 1-s intervals in conscious, freely behaving rats. Results indicate that feeding is associated with an increase of MBH glutamate concentration that occurs within 1-2 s of oral contact with a food pellet, and the glutamate response to a palatable high-fat pellet is greatly exaggerated relative to chow. In contrast, glutamate responses were not observed during water ingestion or other observed behaviors. These findings indicate that feeding is associated with rapid release of glutamate in the MBH, that this release is exaggerated with an obesogenic food, and that this response is likely stimulated by orosensory factors.
    Molecular metabolism. 01/2013; 2(2):116-22.
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    ABSTRACT: Recent evidence suggests that central leptin administration fully normalizes hyperglycemia in a rodent model of uncontrolled insulin-deficient diabetes by reducing hepatic glucose production (HGP) and by increasing glucose uptake. The current studies were undertaken to determine whether brain-derived neurotrophic factor (BDNF) action in the brain lowers blood glucose in uncontrolled insulin-deficient diabetes, and to investigate the mechanisms mediating this effect. Adult male rats implanted with cannulas to either the lateral cerebral ventricle or the ventromedial hypothalamic nucleus (VMN) received either vehicle or streptozotocin to induce uncontrolled insulin-deficient diabetes. Three days later, animals received daily intracerebroventricular or intra-VMN injections of either BDNF or its vehicle. We found that repeated daily intracerebroventricular administration of BDNF attenuated diabetic hyperglycemia independent of changes in food intake. Instead, using tracer dilution techniques during a basal clamp, we found that BDNF lowered blood glucose levels by potently suppressing HGP, without affecting tissue glucose uptake, an effect associated with normalization of both plasma glucagon levels and hepatic expression of gluconeogenic genes. Moreover, BDNF microinjection directly into the VMN also lowered fasting blood glucose levels in uncontrolled insulin-deficient diabetes, but this effect was modest compared with intracerebroventricular administration. We conclude that central nervous system BDNF attenuates diabetic hyperglycemia via an insulin-independent mechanism. This action of BDNF likely involves the VMN and is associated with inhibition of glucagon secretion and a decrease in the rate of HGP.
    Diabetes 12/2012; · 7.90 Impact Factor
  • Thomas H Meek, Gregory J Morton
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    ABSTRACT: Diabetes is a major worldwide problem. Despite some progress in the development of new antidiabetic agents, the ability to maintain tight glycemic control in order to prevent renal, retinal, and neuropathic complications of diabetes without adverse complications still remains a challenge. Recent evidence suggests, however, that in addition to playing a key role in the regulation of energy homeostasis, the adiposity hormone leptin also plays an important role in the control of glucose metabolism via its actions in the brain. This review examines the role of leptin action in the central nervous system and the mechanisms whereby leptin mediates its effects to regulate glucose metabolism. These findings suggest that defects or dysfunction in leptin signaling may contribute to the etiology of diabetes and raise the possibility that either leptin or downstream targets of leptin may have therapeutic potential for the treatment of diabetes.
    Indian journal of endocrinology and metabolism. 12/2012; 16(Suppl 3):S534-42.
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    ABSTRACT: Despite the suggestion that reduced energy expenditure may be a key contributor to the obesity pandemic, few studies have tested whether acutely reduced energy expenditure is associated with a compensatory reduction in food intake. The homeostatic mechanisms that control food intake and energy expenditure remain controversial and are thought to act over days to weeks. We evaluated food intake in mice using two models of acutely decreased energy expenditure: 1) increasing ambient temperature to thermoneutrality in mice acclimated to standard laboratory temperature or 2) exercise cessation in mice accustomed to wheel running. Increasing ambient temperature (from 21 °C to 28 °C) rapidly decreased energy expenditure, demonstrating that thermoregulatory energy expenditure contributes to both light cycle (40 ± 1%) and dark cycle energy expenditure (15 ± 3%) at normal ambient temperature (21 °C). Reducing thermoregulatory energy expenditure acutely decreased food intake primarily during the light cycle (65 ± 7%), thus conflicting with the delayed compensation model, but did not alter spontaneous activity. Acute exercise cessation decreased energy expenditure only during the dark cycle (14 ± 2% at 21 °C; 21 ± 4% at 28 °C), while food intake was reduced during the dark cycle (0.9 ± 0.1 g) in mice housed at 28 °C, but during the light cycle (0.3 ± 0.1 g) in mice housed at 21 °C. Cumulatively, there was a strong correlation between the change in daily energy expenditure and the change in daily food intake (R(2) = 0.51, p<0.01). We conclude that acutely decreased energy expenditure decreases food intake suggesting that energy intake is regulated by metabolic signals that respond rapidly and accurately to reduced energy expenditure.
    PLoS ONE 01/2012; 7(8):e41473. · 3.73 Impact Factor
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    ABSTRACT: Growing evidence suggests that oxytocin plays an important role in the regulation of energy balance and that central oxytocin administration induces weight loss in diet-induced obese (DIO) animals. To gain a better understanding of how oxytocin mediates these effects, we examined feeding and neuronal responses to oxytocin in animals rendered obese following exposure to either a high-fat (HFD) or low-fat diet (LFD). Our findings demonstrate that peripheral administration of oxytocin dose-dependently reduces food intake and body weight to a similar extent in rats maintained on either diet. Moreover, the effect of oxytocin to induce weight loss remained intact in leptin receptor-deficient Koletsky (fa(k)/fa(k)) rats relative to their lean littermates. To determine whether systemically administered oxytocin activates hindbrain areas that regulate meal size, we measured neuronal c-Fos induction in the nucleus of the solitary tract (NTS) and area postrema (AP). We observed a robust neuronal response to oxytocin in these hindbrain areas that was unexpectedly increased in rats rendered obese on a HFD relative to lean, LFD-fed controls. Finally, we report that repeated daily peripheral administration of oxytocin in DIO animals elicited a sustained reduction of food intake and body weight while preventing the reduction of energy expenditure characteristic of weight-reduced animals. These findings extend recent evidence suggesting that oxytocin circumvents leptin resistance and induces weight-loss in DIO animals through a mechanism involving activation of neurons in the NTS and AP, key hindbrain areas for processing satiety-related inputs.
    AJP Endocrinology and Metabolism 01/2012; 302(1):E134-44. · 4.51 Impact Factor
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    ABSTRACT: Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control.
    The Journal of clinical investigation 12/2011; 122(1):153-62. · 15.39 Impact Factor
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    ABSTRACT: Childhood obesity is associated with type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD). Recent studies have found associations between vitamin D deficiency (VDD), insulin resistance (IR), and NAFLD among overweight children. To further explore mechanisms mediating these effects, we fed young (age 25 days) Sprague-Dawley rats with a low-fat diet (LFD) alone or with vitamin D depletion (LFD+VDD). A second group of rats was exposed to a Westernized diet (WD: high-fat/high-fructose corn syrup) that is more typically consumed by overweight children, and was either replete (WD) or deficient in vitamin D (WD+VDD). Liver histology was assessed using the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) scoring system and expression of genes involved in inflammatory pathways were measured in liver and visceral adipose tissue after 10 weeks. In VDD groups, 25-OH-vitamin D levels were reduced to 29% (95% confidence interval [CI]: 23%-36%) compared to controls. WD+VDD animals exhibited significantly greater hepatic steatosis compared to LFD groups. Lobular inflammation as well as NAFLD Activity Score (NAS) were higher in WD+VDD versus the WD group (NAS: WD+VDD 3.2 ± 0.47 versus WD 1.50 ± 0.48, P < 0.05). Hepatic messenger RNA (mRNA) levels of Toll-like receptors (TLR)2, TLR4, and TLR9, as well as resistin, interleukins (IL)-1β, IL-4, and IL-6 and oxidative stress marker heme oxygenase (HO)-1, were higher in WD+VDD versus WD animals (P < 0.05). Logistic regression analyses showed significant associations between NAS score and liver mRNA levels of TLRs 2, 4, and 9, endotoxin receptor CD14, as well as peroxisome proliferator activated receptor (PPAR)γ, and HO-1. Conclusion: VDD exacerbates NAFLD through TLR-activation, possibly by way of endotoxin exposure in a WD rat model. In addition it causes IR, higher hepatic resistin gene expression, and up-regulation of hepatic inflammatory and oxidative stress genes.
    Hepatology 10/2011; 55(4):1103-11. · 12.00 Impact Factor
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    ABSTRACT: Proinflammatory activation of Kupffer cells is implicated in the effect of high-fat feeding to cause liver insulin resistance. We sought to determine whether reduced endothelial nitric oxide (NO) signaling contributes to the effect of high-fat feeding to increase hepatic inflammatory signaling and if so, whether this effect 1) involves activation of Kupffer cells and 2) is ameliorated by increased NO signaling. Effect of NO/cGMP signaling on hepatic inflammation and on isolated Kupffer cells was examined in C57BL/6 mice, eNos(-/-) mice, and Vasp(-/-) mice fed a low-fat or high-fat diet. We show that high-fat feeding induces proinflammatory activation of Kupffer cells in wild-type mice coincident with reduced liver endothelial nitric oxide synthase activity and NO content while, conversely, enhancement of signaling downstream of endogenous NO by phosphodiesterase-5 inhibition protects against high fat-induced inflammation in Kupffer cells. Furthermore, proinflammatory activation of Kupffer cells is evident in eNos(-/-) mice even on a low-fat diet. Targeted deletion of vasodilator-stimulated phosphoprotein (VASP), a key downstream target of endothelially derived NO, similarly predisposes to hepatic and Kupffer cell inflammation and abrogates the protective effect of NO signaling in both macrophages and hepatocytes studied in a cell culture model. These results collectively imply a physiological role for endothelial NO to limit obesity-associated inflammation and insulin resistance in hepatocytes and support a model in which Kupffer cell activation during high-fat feeding is dependent on reduced NO signaling. Our findings also identify the NO/VASP pathway as a novel potential target for the treatment of obesity-associated liver insulin resistance.
    Diabetes 09/2011; 60(11):2792-801. · 7.90 Impact Factor
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    ABSTRACT: Leptin has been shown to reduce hyperglycemia in rodent models of type 1 diabetes. We investigated the effects of leptin administration in University of California, Davis, type 2 diabetes mellitus (UCD-T2DM) rats, which develop adult-onset polygenic obesity and type 2 diabetes. Animals that had been diabetic for 2 mo were treated with s.c. injections of saline (control) or murine leptin (0.5 mg/kg) twice daily for 1 mo. Control rats were pair-fed to leptin-treated animals. Treatment with leptin normalized fasting plasma glucose and was accompanied by lowered HbA1c, plasma glucagon, and triglyceride concentrations and expression of hepatic gluconeogenic enzymes compared with vehicle (P < 0.05), independent of any effects on body weight and food intake. In addition, leptin-treated animals exhibited marked improvement of insulin sensitivity and glucose homeostasis compared with controls, whereas pancreatic insulin content was 50% higher in leptin-treated animals (P < 0.05). These effects coincided with activation of leptin and insulin signaling pathways and down-regulation of the PKR-like endoplasmic reticulum (ER) kinase/eukaryotic translation inhibition factor 2α (PERK-eIF2α) arm of ER stress in liver, skeletal muscle, and adipose tissue as well as increased pro-opiomelanocortin and decreased agouti-related peptide in the hypothalamus. In contrast, several markers of inflammation/immune function were elevated with leptin treatment in the same tissues (P < 0.05), suggesting that the leptin-mediated increase of insulin sensitivity was not attributable to decreased inflammation. Thus, leptin administration improves insulin sensitivity and normalizes fasting plasma glucose in diabetic UCD-T2DM rats, independent of energy intake, via peripheral and possibly centrally mediated actions, in part by decreasing circulating glucagon and ER stress.
    Proceedings of the National Academy of Sciences 08/2011; 108(35):14670-5. · 9.74 Impact Factor
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    Gregory J Morton, Michael W Schwartz
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    ABSTRACT: The regulation of body fat stores and blood glucose levels is critical for survival. This review highlights growing evidence that leptin action in the central nervous system plays a key role in both processes. Investigation into underlying mechanisms has begun to clarify the physiological role of leptin in the control of glucose metabolism and raises interesting new possibilities for the treatment of diabetes and related disorders.
    Physiological Reviews 04/2011; 91(2):389-411. · 30.17 Impact Factor
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    ABSTRACT: Patients with craniopharyngioma (CP), a tumor located in the pituitary and/or hypothalamus, are susceptible to developing obesity and many metabolic complications. The study aim was to create a rodent model that mimics the complex neuroanatomical and metabolic disturbances commonly seen in obese CP patients. We compared the metabolic phenotype of animals with three distinct types of hypothalamic lesions: 1) destruction of the arcuate nucleus (ARC) induced by monosodium glutamate (MSG), 2) electrolytic lesion of the adjacent ventromedial nucleus (VMN) alone, 3) both the VMN and dorsomedial nucleus (DMN), or a 4) combined medial hypothalamic lesion (CMHL) affecting the VMN, DMN, and the ARC. Only the CMHL model exhibited all key features observed in patients with hypothalamic obesity induced by CP. These features included excessive weight gain due to increased adiposity, increased food intake, and pronounced hyperinsulinemia and hyperleptinemia. Similar to characteristics of patients with CP, CMHL animals exhibited reduced plasma levels of alpha-melanocyte stimulating hormone and reduced ambulatory activity compared with weight-matched controls. Therefore, the CMHL model best mimics the complex metabolic abnormalities observed in obese CP patients compared with lesions to other hypothalamic areas and provides a foundation for future pharmacological approaches to treat obesity in children with hypothalamic damage.
    Pediatric Research 03/2011; 69(3):230-6. · 2.67 Impact Factor
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    ABSTRACT: The brain has emerged as a target for the insulin-sensitizing effects of several hormonal and nutrient-related signals. The current studies were undertaken to investigate mechanisms whereby leptin lowers circulating blood glucose levels independently of insulin. After extending previous evidence that leptin infusion directly into the lateral cerebral ventricle ameliorates hyperglycemia in rats with streptozotocin-induced uncontrolled diabetes mellitus, we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic β-cells. Instead, leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency. This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin.
    Endocrinology 02/2011; 152(2):394-404. · 4.72 Impact Factor
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    ABSTRACT: Mechanisms regulating spontaneous physical activity remain poorly characterized despite evidence of influential genetic and acquired factors. We evaluated ambulatory activity and wheel running in leptin-deficient ob/ob mice and in wild-type mice rendered hypoleptinemic by fasting in both the presence and absence of subcutaneous leptin administration. In ob/ob mice, leptin treatment to plasma levels characteristic of wild-type mice acutely increased both ambulatory activity (by 4,000 ± 200 beam breaks/dark cycle, P < 0.05) and total energy expenditure (TEE; by 0.11 ± 0.01 kcal/h during the dark cycle, P < 0.05) in a dose-dependent manner and acutely increased wheel running (+350%, P < 0.05). Fasting potently increased ambulatory activity and wheel running in wild-type mice (AA: +25%, P < 0.05; wheel running: +80%, P < 0.05), and the effect of fasting was more pronounced in ob/ob mice (AA: +400%, P < 0.05; wheel running: +1,600%, P < 0.05). However, unlike what occurred in ad libitum-fed ob/ob mice, physiological leptin replacement attenuated or prevented fasting-induced increases of ambulatory activity and wheel running in both wild-type and ob/ob mice. Thus, plasma leptin is a physiological regulator of spontaneous physical activity, but the nature of leptin's effect on activity is dependent on food availability.
    AJP Endocrinology and Metabolism 11/2010; 300(2):E392-401. · 4.51 Impact Factor

Publication Stats

3k Citations
255 Downloads
4k Views
525.27 Total Impact Points

Institutions

  • 2001–2013
    • University of Washington Seattle
      • • Department of Medicine
      • • Division of Metabolism, Endocrinology and Nutrition
      Seattle, WA, United States
  • 2011
    • Seattle Children’s Research Institute
      Seattle, Washington, United States
  • 2010
    • Vanderbilt University
      Nashville, Michigan, United States
  • 2008
    • Wayne State University
      • Department of Psychiatry and Behavioral Neurosciences
      Detroit, MI, United States
    • University of Everett Washington
      Seattle, Washington, United States
  • 2006
    • Stanford University
      • Division of General Pediatrics
      Stanford, CA, United States
  • 2004
    • Howard Hughes Medical Institute
      Maryland, United States
  • 1999–2000
    • Deakin University
      • School of Exercise and Nutrition Sciences
      Geelong, Victoria, Australia