Metabolic responses to leptin in obese db/db mice are strain dependent

Obese, diabetic C57BL/Ks db/db mice that lack the long-form leptin receptor exhibit no decrease in body weight or food intake when treated with leptin. Here we compared responses to leptin in two strains of db/db mice: C57BL/6J mice that are hyperglycemic and hyperinsulinemic and C57BL/Ks that are hyperglycemic and normo- or hypoinsulinemic. Chronic intraperitoneal infusion of 10 microgram leptin/day partially reversed hyperglycemia in C57BL/6J male mice but exaggerated the diabetic state of female mice. Bolus intraperitoneal injections of 40 microgram leptin/day did not effect glucose in either strain of male db/db mice, whereas chronic intraperitoneal infusion of 20 microgram leptin/day significantly reduced fasting blood glucose in male mice from both strains, especially C57BL/6J mice. Food intake, body weight, rectal temperature, and body fat did not change. Chronic intraperitoneal infusion of 10 microgram leptin/day significantly reduced body fat in lean db/+ C57BL/6J but not in C57BL/Ks mice. Thus peripherally administered leptin is active in mice that have only short-form leptin receptors, and the response is dependent on the method of leptin administration and the background strain.     

The role of T cell subsets and cytokines in the pathogenesis of Helicobacter pylori gastritis in mice

Gastritis due to Helicobacter pylori in mice and humans is considered a Th1-mediated disease, but the specific cell subsets and cytokines involved are still not well understood. The goal of this study was to investigate the immunopathogenesis of H. pylori-induced gastritis and delayed-type hypersensitivity (DTH) in mice. C57BL/6-Prkdc(scid) mice were infected with H. pylori and reconstituted with CD4+, CD4-depleted, CD4+CD45RB(high), or CD4+CD45RB(low) splenocytes from wild-type C57BL/6 mice or with splenocytes from C57BL/6(IFN-gamma-/-) or C57BL/6(IL-10-/-) mice. Four or eight weeks after transfer, DTH to H. pylori Ags was determined by footpad injection; gastritis and bacterial colonization were quantified; and IFN-gamma secretion by splenocytes in response to H. pylori Ag was determined. Gastritis and DTH were present in recipients of unfractionated splenocytes, CD4+ splenocytes, and CD4+CD45RB(high) splenocytes, but absent in the other groups. IFN-gamma secretion in response to H. pylori Ags was correlated with gastritis, although splenocytes from all groups of mice secreted some IFN-gamma. Gastritis was most severe in recipients of splenocytes from IL-10-deficient mice, and least severe in those given IFN-gamma-deficient splenocytes. Bacterial colonization in all groups was inversely correlated with gastritis. These data indicate that 1) CD4+ T cells are both necessary and sufficient for gastritis and DTH due to H. pylori in mice; 2) high expression of CD45RB is a marker for gastritis-inducing CD4+ cells; and 3) IFN-gamma contributes to gastritis and IL-10 suppresses it, but IFN-gamma secretion alone is not sufficient to induce gastritis. The results support the assertion that H. pylori is mediated by a Th1-biased cellular immune response.     

Multidrug resistance gene deficient (mdr1a–/–) mice have an altered caecal microbiota that precedes the onset of intestinal inflammation

Aim:  To compare caecal microbiota from mdr1a ^–/– and wild type (FVB) mice to identify differences in the bacterial community that could influence the intestinal inflammation.
Methods and Results:  Caecal microbiota of mdr1a ^–/– and FVB mice were evaluated at 12 and 25 weeks of age using denaturing gradient gel electrophoresis (DGGE) and quantitative real-time PCR. DGGE fingerprints of FVB and mdr1a ^–/– mice (with no intestinal inflammation) at 12 weeks revealed differences in the presence of DNA fragments identified as Bacteroides fragilis , B. thetaiotaomicron , B. vulgatus and an uncultured alphaproteobacterium. Escherichia coli and Acinetobacter sp. were only identified in DGGE profiles of mdr1a ^–/– mice at 25 weeks (with severe intestinal inflammation), which also had a lower number of total bacteria in the caecum compared with FVB mice at same age.
Conclusions:  Differences found in the caecal microbiota of FVB and mdr1a ^–/– mice (12 weeks) suggest that the lack of Abcb1 transporters in intestinal cells due to the disruption of the mdr1a gene might lead to changes in the caecal microbiota. The altered microbiota along with the genetic defect could contribute to the development of intestinal inflammation in mdr1a ^–/– mice.
Significance and Impact of the Study:  Differences in caecal microbiota of mdr1a ^–/– and FVB mice (12 weeks) suggest genotype specific colonization. The results provide evidence that Abcb1 transporters may regulate host interactions with commensal bacteria. Future work is needed to identify the mechanisms involved in this possible cross-talk between the host intestinal cells and microbiota.     

Deletion of agouti-related protein blunts ethanol self-administration and binge-like drinking in mice

The melanocortin (MC) system is composed of peptides that are cleaved from the polypeptide precursor proopiomelanocortin (POMC). Recent pharmacological and genetic evidence suggests that melanocortin receptor (MCR) signaling modulates neurobiological responses to ethanol and ethanol intake. Agouti-related protein (AgRP) is synthesized by neurons in the arcuate nucleus of the hypothalamus and is a natural antagonist of MCRs. Because central administration of the functionally active AgRP fragment AgRP-(83–132) increases ethanol intake by C57BL/6 J mice, we determined if mutant mice lacking normal production of AgRP (AgRP^−/−) and maintained on a C57BL/6 J genetic background would show reduced self-administration of ethanol relative to littermate wild-type (AgRP^+/+) mice. AgRP^−/— mice showed reduced 8% (v/v) ethanol-reinforced lever-pressing behavior relative to AgRP^+/+ mice in daily 2-h sessions, but normal sucrose-, saccharin- and water-reinforced lever-pressing. Similarly, AgRP^−/− mice showed reduced consumption of 8% ethanol in a two-bottle limited access test (2 h/day), although this effect was largely sex-dependent. Using drinking-in-the-dark (DID) procedures, AgRP^−/— mice showed blunted binge-like drinking of 20% (v/v) ethanol which was associated with lower blood ethanol levels (85 mg/dl) relative to AgRP^+/+ mice (133 mg/dl) after 4 h of intake. AgRP^−/− mice showed normal ethanol metabolism and did not show altered sensitivity to the sedative effects of ethanol. These observations with genetically altered mice are consistent with previous pharmacological data and suggest that endogenous AgRP signaling modulates the reinforcing properties of ethanol and binge-like ethanol drinking.     

Helicobacter pylori infection in wild-type and cytokine-deficient C57BL/6 and BALB/c mouse mutants

Helicobacter pylori causes gastroduodenal ulcer disease in humans. T lymphocytes and their cytokines are thought to play a substantial role in the control of H. pylori infection. To determine the importance of T helper (Th) cytokines and background genes we investigated the natural course of H. pylori infection in BALB/c and C57BL/6 wild-type or mutant mice deficient for either interleukin (IL)-4 or interferon (IFN)-gamma. H. pylori SPM 326 persisted for at least six months in C57BL/6 but was cleared by BALB/c wild-type mice nine weeks postinfection. H. pylori was recovered more frequently from IFN-gamma(-/-) BALB/c and IFN-gamma( -/-) C57BL/6 mice than from the respective wild-type animals. In contrast, IL-4 deficiency had no detectable effect on H. pylori recovery rates from either strain of mice. Our data suggest a protective role of IFN-gamma by mediating inflammation in murine H. pylori infection. In addition, our data emphasize that background genes which differ between BALB/c and C57BL/6 mice regulate the clearance of H. pylori.     

Helicobacter pylori-induced mucosal inflammation is Th1 mediated and exacerbated in IL-4, but not IFN-gamma, gene-deficient mice

To elucidate the pathogenesis of Helicobacter pylori-associated gastritis, we studied immune responses of C57BL/6J wild-type (WT), SCID, and gene deficient (IFN-gamma-/- and IL-4-/-) mice following infection with a pathogenic isolate of H. pylori (SPM326). During early infection in WT mice, mononuclear and polymorphonuclear cells accumulated in the gastric lamina propria, and the numbers of cells in the inflamed mucosa expressing IFN-gamma, but not IL-4, mRNA rose significantly (p < 0.005), consistent with a local Th1 response. Splenic T cells from the same infected WT mice produced high levels of IFN-gamma, no detectable IL-4, and low amounts of IL-10 following in vitro H. pylori urease stimulation, reflecting a systemic Th1 response. Infected C57BL/6J SCID mice did not develop gastric inflammation despite colonization by many bacteria. Infected C57BL/10J and BALB/c mice also did not develop gastric inflammation and displayed a mixed Th1/Th2 splenic cytokine profile. These data imply a major role for the Th1 cytokine IFN-gamma in H. pylori-associated gastric inflammation in C57BL/6J mice. Compared with WT animals, infected IL-4-/- animals had more severe gastritis and higher levels of IFN-gamma production by urease-stimulated splenocytes (p < 0.01), whereas IFN-gamma-/- mice exhibited no gastric inflammation and higher levels of IL-4 production by stimulated splenocytes. These findings establish C57BL/6J mice as an important model for H. pylori infection and demonstrate that up-regulated production of IFN-gamma, in the absence of the opposing effects of IL-4 (and possibly IL-10), plays a pivotal role in promoting H. pylori-induced mucosal inflammation.     

Exocytotic release of dopamine in ventral tegmental area slices from C57BL/6 and dopamine transporter knockout mice

The present study used voltammetry to ascertain whether electrically stimulated somatodendritic dopamine release in ventral tegmental area slices from C57BL/6 and dopamine transporter knockout mice was due to exocytosis or dopamine transporter reversal, as has been debated. The maximal concentration of electrically evoked dopamine release was similar between ventral tegmental area slices from dopamine transporter knockout and C57BL/6 mice. Dopamine transporter blockade (10 μM nomifensine) in slices from C57BL/6 mice inhibited dopamine uptake but did not alter peak evoked dopamine release. In addition, dopamine release and uptake kinetics in ventral tegmental area slices from dopamine transporter knockout mice were unaltered by the norepinephrine transporter inhibitor, desipramine (10 μM), or the serotonin transporter inhibitor, fluoxetine (10 μM). Furthermore, maximal dopamine release in ventral tegmental area slices from both C57BL/6 and dopamine transporter knockout mice was significantly decreased in response to Na⁺ channel blockade by 1 μM tetrototoxin, removal of Ca²⁺ from the perfusion media and neuronal vesicular monoamine transporter inhibition by RO-04-1284 (10 μM) or tetrabenazine (10 and 100 μM). Finally, the glutamate receptor antagonists AP-5 (50 and 100 μM) and CNQX (20 and 50 μM) had no effect on peak somatodendritic dopamine release in C57BL/6 mice. Overall, these data suggest that similar mechanisms, consistent with exocytosis, govern electrically evoked dopamine release in ventral tegmental area slices from C57BL/6 and dopamine transporter knockout mice.     

Evidence for an interaction between leptin, T cell costimulatory antigens CD28, CTLA-4 and CD26 (dipeptidyl peptidase IV) in BCG-induced immune responses of leptin- and leptin receptor-deficient mice

We assessed changes of the enzyme dipeptidyl peptidase IV (DPP IV, CD26) in the context of leptin or leptin receptor deficiency. C57BL/6 mice, Leptin-deficient mice (ob/ob mice, B6.V-Lep) and Leptin-receptor-deficient mice (db/db mice, B6.Cg-m+/+Lepr) were infected with B. Calmette-Guerin (BCG) and sacrificed three days later. DPP IV activity in serum was higher in ob/ob mice and in db/db mice than in wild-type mice. The expression of DPP IV/CD26 on splenocytes was higher in ob/ob mice than in wild-type animals, and lower in db/db mice, and decreased upon stimulation with BCG in ob/ob mice only. Several T cell antigens including CTLA-4 were expressed aberrantly in ob/ob and in db/db mice. Our observations provide evidence for a relationship between DPP IV and leptin.     

E- and P-selectin are not required for the development of experimental autoimmune encephalomyelitis in C57BL/6 and SJL mice

In multiple sclerosis and in its animal model experimental autoimmune encephalomyelitis (EAE), inflammatory cells migrate across the endothelial blood-brain barrier (BBB) and gain access to the CNS. It is well-established that alpha4 integrins are actively involved in leukocyte recruitment across the BBB during EAE. In contrast, the role of endothelial E- and P-selectin in this process has been a controversial issue. In this study, we demonstrate that P-selectin protein can be detected in meningeal blood vessel endothelial cells in healthy SJL and C57BL/6 mice and on rare parenchymal CNS blood vessels in C57BL/6, but not SJL, mice. During EAE, expression of P-selectin but not E-selectin was found up-regulated on inflamed CNS microvessels surrounded by inflammatory infiltrates irrespective of their meningeal or parenchymal localization with a more prominent immunostaining detected in C57BL/6 as compared with SJL mice. P-selectin immunostaining could be localized to CNS endothelial cells and to CD41-positive platelets adhering to the vessel wall. Despite the presence of P-selectin in wild-type mice, E/P-selectin-deficient SJL and C57BL/6 mice developed clinical EAE indistinguishable from wild-type mice. Absence of E- and P-selectin did neither influence the activation of myelin-specific T cells nor the composition of the cellular infiltrates in the CNS during EAE. Finally, endothelial-specific tetracycline-inducible expression of E-selectin at the BBB in transgenic C57BL/6 mice did not alter the development of EAE. Thus, E- and P-selectin are not required for leukocyte recruitment across the BBB and the development of EAE in C57BL/6 and in SJL mice.     

IL-17 is involved in bone resorption in mouse periapical lesions

Periapical lesions are induced by bacterial infection of the dental pulp and result in destruction of the surrounding alveolar bone. Although various immunological studies concerning periapical bone resorption have been reported, the role of cytokines in the formation of periapical lesions remains unclear. In this study, the role of IL-17A in periapical lesions in mice was investigated. Normal C57BL/6, IFN-γ^−/−, TNF-α^−/−, and IL-17A^−/− mice were subjected to pulp exposure and infected with Prevotella intermedia (ATCC25611) and Porphyromonas gingivalis (ATCC33277) in the mandibular first molar. Periapical lesions were determined by μCT on day 21 after infection, and 3D visual construction was performed using 3D picture quantification software. The expression of IL-17A mRNA in periapical lesions was determined by the RT-PCR and real-time RT-PCR method. Periapical lesions developed in wild-type, IFN-γ^−/−, and TNF-α^−/− mice after infection with P. intermedia and P. gingivalis . However, periapical lesions were not observed in IL-17A^−/− mice. The expression of IL-17A mRNA was significantly induced in periapical lesions of wild-type mice after infection. These results suggest that IL-17A, but not IFN-γ or TNF-α, plays an important role in the formation of periapical lesions.     

Importance of the host genetic background on immune responses to Helicobacter pylori infection and therapeutic vaccine efficacy

In order to investigate the role of host factors in Helicobacter pylori infection and immunity, two different strains of inbred mice, C57BL/6 and BALB/c, were infected with a standard H. pylori strain, SS1. A month later, infected mice were immunized orally with whole-cell lysates of H. pylori SS1 and cholera toxin on days 1, 3, 6, 30, and 54. Ten days after the last immunization, mice were sacrificed and the stomach was collected to assess H. pylori colonization density by quantitative culture. H. pylori SS1 colonization was significantly greater in C57BL/6 than in BALB/c (P<0.02 and P<0.003 at 2 and 13 weeks post-inoculation, respectively). Colonization in C57BL/6 persisted at equivalent levels for 13 weeks but the colonization density in BALB/c decreased significantly during this period. In contrast to the pattern of bacterial colonization, antibody responses following H. pylori SS1 infection were greater in BALB/c than in C57BL/6, suggesting that host factors may modulate the immune responses to H. pylori infection. Following therapeutic immunization, H. pylori colonization in BALB/c mice was also significantly reduced (P<0.03), while no significant differences in bacterial density were observed in C57BL/6. These observations collectively demonstrate the great importance of host factors in H. pylori infection and the development of effective immune responses.     

Inhibition of Helicobacter pylori Infection in Humans by Lactobacillus reuteri ATCC 55730 and Effect on Eradication Therapy: A Pilot Study

Background:  Several studies report an inhibitory effect of probiotics on Helicobacter pylori .
Aim:  To test whether Lactobacillus reuteri ATCC 55730 reduces H. pylori intragastric load in vivo, decreases dyspeptic symptoms, and affects eradication rates after conventional treatment.
Materials and Methods:  In a double-blind placebo-controlled study, 40 H. pylori -positive subjects were given L. reuteri once a day for 4 weeks or placebo. All underwent upper endoscopy, ¹³C-urea breath test, and H. pylori stool antigen determination at entry and ¹³C-urea breath test and H. pylori stool antigen (used as both qualitative and semiquantitative markers) after 4 weeks of treatment. Sequential treatment was administered subsequently to all.
Results:  In vivo, L. reuteri reduces H. pylori load as semiquantitatively assessed by both ¹³C-urea breath test δ -value and H. pylori stool antigen quantification after 4 weeks of treatment ( p <  .05). No change was shown in patients receiving placebo. L. reuteri administration was followed by a significant decrease in the Gastrointestinal Symptom Rating Scale as compared to pretreatment value ( p <  .05) that was not present in those receiving placebo ( p =  not significant). No difference in eradication rates was observed.
Conclusions:  L. reuteri effectively suppresses H. pylori infection in humans and decreases the occurrence of dyspeptic symptoms. Nevertheless, it does not seem to affect antibiotic therapy outcome.     

Comparison of T cell cytokines in resistant and susceptible mice infected with virulent Brucella abortus strain 2308

Abstract C57BL/10 and BALB/c mice differ in their abilities to clear infections with the intracellular bacterium Brucella abortus strain 2308. We have previously reported that in vivo neutralization of IL-10 in the susceptible BALB/c mice results in significantly fewer bacteria in their spleens 1 week after infection with 5 × 10³ colony forming units (CFU) of 2308. Here we extend those studies and report a similar effect when IL-4 is neutralized. In contrast, in the more resistant C57BL/10 mice infected with 5 × 10³ CFU, neither neutralization of IL-10 nor IL-4 significantly decreased the level of infection nor did it in either BALB/c or C57BL/10 mice infected with a 1000-fold higher dose of strain 2308. While splenocytes from the later mentioned groups of 1 produced IL-10 in response to stimulation with brucella antigen, they also produced higher levels of interferon (IFN)-γ than those from BALB/c mice infected with the low challenge dose of 5 × 10³ CFU. Results of in vivo neutralization of IFN-γ by monoclonal antibodies (MAb) reported here and elsewhere indicated that IFN-γ is important for control; thus, we postulate that the higher levels of IFN-γ may override the detrimental effects of Th2 cytokines. In vitro studies also showed that macrophages from the more resistant C57BL/10 mice were less susceptible to the ability of IL-10 to decrease anti-brucella activities than were BALB/c macrophages. CD4⁺ T cells were principally responsible for the production of IL-10 in BALB/c but not C57BL/10 splenocyte populations. C57BL/10 splenocytes produced more IFN-γ than those from BALB/c mice in response to stimulation with brucella antigens. These differences between BALB/c and C57BL/10 mice may contribute to the superior capacity of C57BL/10 mice to control infections with B. abortus strain 2308.     

Lactoferrin and desferrioxamine are ineffective in the treatment of Helicobacter pylori infection and may enhance H. pylori growth and gastric inflammation in mice

Aims:  To evaluate the efficacy of bovine lactoferrin (BLf), recombinant human lactoferrin (rHLf) and desferrioxamine against Helicobacter pylori in vitro and in mice and also to determine whether BLf or rHLf alter gastric inflammation.
Methods and Results:  In vitro: Broth dilution susceptibility tests were performed using different concentrations of desferrioxamine, BLf and rHLf. Murine trials: In the prevention trial, C57BL/6 female mice were treated with BLf or rHLF, and then infected with the SS1 strain of H. pylori . In the treatment trial, mice were gavaged with either BLf, rHLf or desferrioxamine. In addition, gastric myeloperoxidase activity (MPO) was measured to assess gastric inflammation. Desferoxamine was found to have a direct bactericidal effect, while BLf and rHLf only partially suppressed H. pylori growth in vitro . However, in both prevention and treatment trials all three forms of treatment failed to reduce H. pylori load in mice. Gastric MPO activity and H. pylori load were noted to be higher with lactoferrin treatments.
Conclusions:  Our study does not support the use of BLf or rHLF in the treatment of human H. pylori infection. Interestingly, H. pylori growth and gastric inflammation appear to be enhanced by lactoferrin treatment.
Significance and Impact of the Study:  The mouse model is ideal for testing novel H. pylori eradicating agents.     

Vaccination with SIVmac239Δnef activates CD4+ T cells in the absence of CD4+ T-cell loss

Background  Pathogenic HIV and SIV infections characteristically deplete central memory CD4⁺ T cells and induce chronic immune activation, but it is controversial whether this also occurs after vaccination with attenuated SIVs and whether depletion or activation of CD4⁺ T-cell play roles in protection against wild-type virus challenge.
Methods  Rhesus macaques were vaccinated with SIVmac239Δnef and quantitative and phenotypic polychromatic flow cytometry analyses were performed on mononuclear cells from blood, lymph nodes and rectal biopsies.
Results  Animals vaccinated with SIVmac239Δnef demonstrated no loss of CD4⁺ T cells in any tissue, and in fact CCR5⁺ and CD28⁺CD95⁺ central memory CD4⁺ T cells were significantly increased. In contrast, CD4⁺ T-cell numbers and CCR5 expression significantly declined in unvaccinated controls challenged with SIVmac239. Also, intracellular Ki67 increased acutely as much as 3-fold over baseline in all tissues after SIVmac239Δnef vaccination then declined following primary infection.
Conclusion  We demonstrated in this study that SIVmac239Δnef vaccination did not deplete CD4⁺ T cells but transiently activated and expanded the memory cell population. However, increases in numbers and activation of memory CD4⁺ T cells did not appear to influence protective immunity.     

Gender Difference of Circulating Ghrelin and Leptin Concentrations in Chronic Helicobacter pylori Infection

Background:  Both ghrelin and leptin are important appetite hormones secreted from the stomach. We examined whether demographic background, Helicobacter pylori infection, or its related gastritis severity could be associated with circulating ghrelin and leptin levels.
Methods:  This study prospectively enrolled 341 dyspeptic patients (196 females, 145 males), who had received endoscopy to provide the gastric specimens over both antrum and corpus for histology reviewed by the updated Sydney's system. The fasting blood sample of each patient was obtained for total ghrelin and leptin analysis.
Results:  Without H. pylori infection, there were similar ghrelin levels between female and male patients. In the H. pylori -infected patients, the males had lower plasma ghrelin levels than females (1053 vs. 1419 pg/mL, p  < .001). Only in males, not in females, the H. pylori infection and its related acute and chronic inflammation scores were significantly associated with a lower ghrelin level ( p  ≤ .04). The multivariate regression disclosed that only the chronic inflammation score independently related to a lower ghrelin level. Only in males, the ghrelin levels ranked in a downward trend for the gastritis feature as with limited-gastritis, with antrum-predominant gastritis, and with corpus-gastritis (1236, 1101, and 977 pg/mL). Leptin level was not related to H. pylori -related gastritis, but positively related to body mass index.
Conclusion:  There should be a gender difference to circulating total ghrelin levels, but not leptin levels, in response to H. pylori infection and its related chronic gastritis.     

Spinal cord degeneration in C57BL/6N mice following induction of experimental parkinsonism with MPTP

We examined neurodegeneration in spinal cord (SC) and role of such extra-nigral degeneration in MPTP-induced experimental parkinsonism in C57BL/6N mice. HPLC-photodiode array analysis confirmed presence of the active neurotoxin MPP⁺ in SC after single injection of MPTP (25 mg/kg, i.p.). Mitochondrial enzyme monoamine oxidase-B (MAO-B) responsible for in vivo conversion of MPTP to MPP⁺ was inhibited in SC by pre-treatment with l -deprenyl, a specific inhibitor of MAO-B. Besides in vitro conversion of MPTP to MPP⁺ occurred by SC mitochondrial preparation, which was inhibited by l -deprenyl implicating SC as a specific target of MPTP-neurotoxicity. Double immunofluorescent labeling and spectrofluorimetric assay via kynuramine oxidation showed MAO-B expression and activity in SC neurons. Localization of dopamine transporter immunoreactivity in SC along with specific uptake of ³H-MPP⁺ by SC synaptosomal preparation further confirmed SC as target of MPTP-neurotoxicity. Compared with control, increased neuronal death on the seventh day in SC of mice injected with MPTP (2 × 25 mg/kg, at 6 h interval) strongly suggested SC degeneration in pre-symptomatic phase of MPTP-induced experimental parkinsonism. Such extra-nigral neurodegeneration in Parkinson's disease indicated novel molecular mechanism preceding nigrostriatal degeneration and suggested designing broad therapeutic intervention for this complex movement disorder.     

Compensation for partial lipectomy in mice with genetic alterations of leptin and its receptor subtypes

One hypothesis for the regulation of total body fat suggests that leptin is a lipostatic feedback signal that acts at brain sites involved in regulation of energy balance. The importance of leptin in recovery from partial surgical lipectomy was tested by performing bilateral epididymal lipectomy or sham surgery on wild-type and leptin-deficient ob/ob mice. Eight weeks later, nonexcised pads of lipectomized mice were increased but total carcass fat was lower than in sham-operated ob/ob mice. In experiment 2, ob/ob mice, wild-type mice, and two db/db mutants, C57BL/6J db(Lepr)/db(Lepr) (BL/6J) mice possessing short-form and circulating leptin receptors and C57BL/6J db(3J)/db(3J) (BL/3J) mice expressing only circulating receptors, were lipectomized or sham operated. Sixteen weeks later, body mass and carcass lipid were not different between sham and lipectomized ob/ob mice, wild-type mice, or BL/6J db/db mice, whereas there was incomplete (decreased carcass fat) but suggestive recovery (increased retroperitoneal fat mass and cell number) in lipectomized BL/3J db/db mice. These data indicate that leptin is not required for the regulation of total body fat.