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The purpose of this systematic review is to analyze the available evidence linking short-chain fatty acids (SCFA) to leptin's levels and production. We performed a systematic review using the PubMed/Medline database including primary articles written in English that measured leptin production or levels as well as SCFA used as an intervention, mechanism or outcome. The search yielded a total of 573 citations; 36 studies were included in the final analysis. The quality of the studies was analyzed through two validated tools based on objective criteria. Overall, the studies presented low risk of bias to construct and statistical validity. However, the majority presented a high risk of attrition and detection bias. In vitro studies (n = 8) consistently demonstrated that SCFA stimulate leptin expression in adipocytes through activation of free fatty acid receptor 3 (FFAR3). In animal studies (n = 24), interventions to modulate high-fat diet outcomes predominantly caused a decrease in circulating leptin levels and increased SCFA, associated with suppressed weight gain. Control of dysbiosis through administration of prebiotics and probiotics also played a role in leptin synthesis in animal studies. In human studies (n = 4) leptin was mainly correlated with adiposity but dysbiosis interfered with this relationship. We conclude that the association between SCFA and leptin remains incompletely understood but occurs mainly through the activation of FFAR3 in adipocytes. However, body fat rather than SCFA remains the main driver for leptin synthesis in vivo. Future studies should aim to better clarify the role of SCFA in regulating leptin production in vivo., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Gestational weight gain (GWG) is an important modifiable factor known to influence fetal outcomes including birth weight and adiposity. Unlike behaviors such as smoking and alcohol consumption, the effect of GWG throughout pregnancy on fetal development and other outcomes has not been extensively studied. The aim of this study was to investigate the relationship of GWG with endocrine factors such as adiponectin, leptin, and C-reactive protein which may be associated with inflammatory response, fetal growth, and adiposity later in life. Data were obtained from the Ulm Birth Cohort Study (UBCS) and the Ulm SPATZ Health Study, two methodologically similar birth cohort studies including newborns and their mothers recruited from 11/2000-11/2001 and 04/2012-05/2013. In the two included birth cohorts we consistently observed statistically significant positive associations between GWG beginning as early as the second trimester with fetal cord blood leptin and stronger association beginning as early as the first trimester with post-delivery maternal serum leptin. Total weight gain exceeding commonly accepted recommended guidelines was consistently associated with higher leptin levels in both cord blood and post-delivery maternal serum. These results suggest a potential pathomechanistic link between fetal environment and surrogate markers of long-term health., Competing Interests: The authors declare no competing financial interests.

Leptin regulates appetite and metabolism but also immunity and inflammation. Although functional leptin receptors (LepR) are expressed on hematopoietic cells, the role of these receptors in regulating immune function in vivo remains controversial. To clarify this issue, we performed bone marrow (BM) transplantation between obese db/db mice, lacking LepR, and wild-type (WT) mice. Results indicate that expression of LepR on BM-derived cells directly, though partially, regulates spleen and thymus cellularity, although the environment of db mice contributes to maintaining reduced cellularity of these organs. Selective expression of LepR on BM-derived cells also modulates leptin and adiponectin levels, with induction of a more favorable adipokine environment in the WT→db/db group. However, LepR signaling in BM-derived cells is not involved in regulation of body weight (BW) and composition, glycemia, hepatosteatosis or adipose tissue inflammation, although it modulates expression of interleukin (IL)-1β in the brain. Finally, data indicate that db mice have an increased susceptibility to irradiation compared to WT mice in terms of BW loss and recovery of leukocyte counts in peripheral blood. Therefore, interpretation of results obtained using BM chimeras between WT and db mice should take into account the difference in radiation sensitivity between the two types of animals.

Leptin is a protein produced by adipocytes (and other cell types) that acts in the brain to regulate appetite and energy expenditure according to the amount of energy stored in adipose tissue. Leptin also exerts a variety of other functions, including important roles as a regulator of immune and inflammatory reactions. The present article is not meant to be a comprehensive review on leptin and immunity, but rather highlights a few controversial issues about leptin's place in the complex network of mediators regulating immune and inflammatory responses. Three issues are discussed: (1) Where am I going, or What is the cellular target of leptin for modulation of immune responses?; (2) Where am I coming from, or Is the cellular source important in determining leptin's effects on immune responses? and (3) What am I doing, or What are leptin's effects on immune and inflammatory responses?

Obesity is associated with increased severity of acute pancreatitis (AP). The cytokines IL-18 and IL-12 are elevated in patients with AP, and IL-18 levels are high in obesity. We aimed to develop a pathologically relevant model to study obesity-associated severe AP. Lean WT and obese leptin-deficient ob/ob mice received two injections of IL-12 plus IL-18. Survival, pancreatic inflammation, and biochemical markers of AP were measured. Dosing with IL-12 plus IL-18 induced 100% lethality in ob/ob mice; no lethality was observed in WT mice. Disruption of pancreatic exocrine tissue and acinar cell death as well as serum amylase and lipase levels were significantly higher in ob/ob than in WT mice. Edematous AP developed in WT mice, whereas obese ob/ob mice developed necrotizing AP. Adipose tissue necrosis and saponification were present in cytokine-injected ob/ob but not in WT mice. Severe hypocalcemia and elevated acute-phase response developed in ob/ob mice. The cytokine combination induced high levels of regenerating protein 1 and pancreatitis-associated protein expression in the pancreas of WT but not of ob/ob mice. To differentiate the contribution of obesity to that of leptin deficiency, mice received short- and long-term leptin replacement therapy. Short-term leptin reconstitution in the absence of major weight loss did not protect ob/ob mice, whereas leptin deficiency in the absence of obesity resulted in a significant reduction in the severity of the pancreatitis. In conclusion, we developed a pathologically relevant model of AP in which obesity per se is associated with increased severity.

Background: Adipokines are involved in the regulation of many inflammatory processes and are present at very high concentrations in cord blood of term infants., Objective: We analysed data of a large prospective birth cohort study to examine whether adiponectin and leptin concentration in cord blood are determinants of wheezing disorders in children within the first 2 years of life., Methods: Seven hundred and forty mothers and their newborns were included in this analysis. Adiponectin and leptin concentrations were measured in cord blood. The cumulative incidence of physician-reported asthma or obstructive bronchitis was recorded during a 2-year follow-up., Results: During the first 2 years of life, asthma or obstructive bronchitis was reported by the caring paediatricians for 157 (19.6%) of the children. We found a strong interaction of cord blood adiponectin and history of atopic disease in the mother with respect to the risk of physician-reported asthma or obstructive bronchitis (P=0.006). Compared with children with cord blood levels in the middle quintile (reference category), the odds ratios for physician-reported asthma or obstructive bronchitis in the bottom quintile and top quintile were 0.14 [95% confidence interval (CI) 0.02-0.90] and 2.12 (95% CI 0.67-6.66), respectively (P for trend=0.0003), among children of mothers with a history of atopy. This association was independent of other established risk factors. Leptin levels in cord blood were not associated with risk of asthma or obstructive bronchitis., Conclusions: In children of mothers with a history of atopy, concentrations of adiponectin in cord blood could play an important role in determining risk of wheezing disorders in early childhood.

Leptin-deficient ob/ob mice exhibit several metabolic and immune abnormalities, including thymus atrophy and markedly reduced inflammatory responses. We evaluated whether transplantation of wild-type (WT) white adipose tissue (WAT) into ob/ob mice could mimic the effect of recombinant leptin administration in normalizing metabolic, immune and inflammatory abnormalities. Female ob/ob mice received a subcutaneous transplantation of WAT obtained from WT littermates. A separate group of ob/ob mice was sham-operated. Despite raising leptin levels to only 15% of those observed in WT mice, WAT transplantation normalized metabolic abnormalities (glycemia, ALT, liver weight) in ob/ob mice and prevented further body weight gain. The transplanted group demonstrated normalization of thymus and spleen cellularity, thymocyte subpopulations and rates of thymocyte apoptosis. In the model of dextran sulfate sodium-induced colitis, WAT transplantation restored inflammation to levels equivalent to those of WT mice. Colonic production of IL-6 and MIP-2 was markedly reduced in the non-transplanted ob/ob group compared to transplanted ob/ob and WT mice. Our data indicate that WAT transplantation is an effective way to normalize metabolic as well as immune and inflammatory parameters in ob/ob mice. The threshold of leptin sufficient to normalize metabolic, immune and inflammatory function is significantly lower than levels present in lean WT mice. Finally, leptin derived exclusively from WAT is sufficient to normalize metabolic, immune and inflammatory parameters in ob/ob mice.

Leptin, a protein produced by adipocytes, exerts several functions, including modulation of the immune response. A report in this issue of the European Journal of Immunology describes for the first time the effect of either leptin receptor deficiency or blockade on murine dendritic cell (DC) maturation, survival and function. The study describes how leptin receptor deficiency/blockade delays DC maturation and promotes apoptosis, shifts the balance between pro- and anti-inflammatory cytokine production, and reduces the ability of DC to stimulate CD4(+) lymphocytes. These exciting novel data add an important piece of evidence to the picture of the role of leptin in immunity and inflammation and generate the possibility that many of the effects of leptin on T lymphocytes might be mediated through DC.

Leptin is a pleiotrophic protein mainly produced by adipocytes that has been implicated as a link between nutritional status and immune function. Severe bacterial infection is associated with elevated plasma levels of leptin. To determine the role of leptin in the host response to bacterial pneumonia leptin deficient ob/ob mice and normal wild-type (WT) mice were intranasally infected with different doses of the Gram-positive pathogen Streptococcus (S.) pneumoniae or the Gram-negative bacterium Klebsiella (K.) pneumoniae. After infection with lower doses of either pathogen ob/ob mice displayed lower pulmonary levels of proinflammatory cytokines, in particular tumor necrosis factor-alpha and chemokines. However, after infection with a higher dose of S. pneumoniae or K. pneumoniae the lung concentrations of these inflammatory mediators did not differ between ob/ob and WT mice. In addition, the extent and severity of lung inflammation, as assessed by semi-quantitative histopathology scores, were similar in both mouse strains. Finally, leptin deficiency did not impact on the bacterial outgrowth in the lungs during either Gram-positive or Gram-negative pneumonia irrespective of the infective dose. These data suggest that although leptin may play a modest role in the regulation of inflammation during bacterial pneumonia, it does not contribute to host defense mechanisms that act to limit the outgrowth of S. pneumoniae or K. pneumoniae in the lower airways.

The development of active tuberculosis after infection with Mycobacterium tuberculosis is almost invariably caused by a persistent or transient state of relative immunodeficiency. Leptin, the product of the obese (ob) gene, is a pleiotropic protein produced mainly by adipocytes and is down-regulated during malnutrition and starvation, conditions closely connected with active tuberculosis. To investigate the role of leptin in tuberculosis, we intranasally infected wild-type (Wt) and leptin-deficient ob/ob mice with live virulent M. tuberculosis. Ob/ob mice displayed higher mycobacterial loads in the lungs after 5 and 10 weeks of infection, although the difference with Wt mice remained 1 log of M. tuberculosis colony forming unit. Nevertheless, ob/ob mice were less able to form well-shaped granuloma and lung lymphocyte numbers were reduced compared with Wt mice early during infection. In addition, ob/ob mice had a reduced capacity to produce the protective cytokine IFNgamma at the site of the infection early during infection and upon antigen-specific recall stimulation, and showed reduced delayed-type hypersensitivity reaction to intra-dermal tuberculin purified protein derivative. Leptin replacement restored the reduced IFNgamma response observed in ob/ob mice. Mortality did not differ between ob/ob and Wt mice. These data suggest that leptin plays a role in the early immune response to pulmonary tuberculosis.

The role of leptin in the immune system has been well established. While adipocytes represent the major source, leptin production by lymphocytes, infiltrating at the site of inflammation, was recently demonstrated. However, the significance of this locally released leptin remains unresolved. In the present study, two models in which absence of leptin-signalling is associated with protection were employed: the model of ConA-induced hepatitis and the CD4(+)CD45Rb(high) transfer model of colitis. For the ConA model, scid mice were reconstituted with either WT or leptin-deficient (ob/ob) CD4(+) T cells. Eight weeks post transfer, ConA was injected and serum ALT, TNFalpha, leptin as well as liver mononuclear cell activation and histological signs of inflammation were evaluated. No difference between recipients of WT or ob/ob cells was observed for any of the parameters evaluated. In the second model, either WT or ob/ob CD4(+)CD45Rb(high) cells were transferred into scid mice. No histological differences were detected, although recipients of ob/ob cells showed higher weight loss compared to recipients of WT cells. Spontaneous production of IL-6 from colon cultures obtained from recipients of ob/ob cells was reduced compared to recipients of WT cells, whereas stimulation of lamina propria lymphocytes with leptin resulted in a higher IFNgamma release in recipients of ob/ob cells compared to recipients of WT cells. In conclusion, the present study provides evidence that T cell-derived leptin does not play a major role in the regulation of the inflammatory process, indicating that the adipose tissue is the critical player in the immune-modulating effects of leptin.

Concanavalin A-induced hepatotoxicity was compared in lipodystrophic aP2-nSREBP-1c transgenic mice (LD mice) lacking adipose tissue, obese leptin-deficient ob/ob mice, and lean wild-type (WT) mice. Serum leptin and adiponectin were low in LD mice, whereas ob/ob mice had undetectable leptin, but high adiponectin. Protection from hepatotoxicity was observed in ob/ob, but not in LD mice, despite low cytokine levels and reduced T cell activation and hepatic natural killer T cells in both groups. Administration of adiponectin protected LD mice from hepatotoxicity without altering cytokine levels. In contrast, administration of leptin heightened disease susceptibility by restoring cytokine production. Neutralization of TNF alpha protected LD mice from liver damage. Increased in vivo susceptibility to the hepatotoxic effect of TNF alpha was observed in LD mice. In vitro, adiponectin protected primary hepatocytes from TNF alpha-induced death, whereas leptin had no protective effect. In conclusion, although leptin increases susceptibility to hepatotoxicity by regulating cytokine production and T cell activation, adiponectin protects hepatocytes from TNF alpha-induced death.

Food restriction and weight loss result in reduced plasma leptin, which is associated with a pleiotropic biologic response. However, because weight loss itself is also associated with changes in numerous other humoral and metabolic signals, it can be difficult to determine the precise features of the biologic response to acute leptin deficiency. To study this response in the absence of changes in nutritional state, we have developed a protocol that allows such analysis in normal, non-food-restricted animals. Wild-type mice are treated with high-dose leptin until fat mass is depleted and, as a consequence, endogenous leptin production is reduced. At this point, exogenous leptin is abruptly withdrawn, thus inducing a state of leptin deficiency in otherwise normal mice. Leptin deficiency is sustained by feeding the animals only as much as they consumed voluntarily before leptin withdrawal. The biologic response to leptin deficiency induced in this manner includes altered neuropeptide levels, decreased energy expenditure, and impaired reproductive and immune function. Replacement of leptin at physiological concentrations after withdrawal of high-dosage leptin blunts, but does not completely block, the hyperphagia and weight regain caused by acute leptin deficiency, nor does it correct the resulting reproductive and immune dysfunction. This suggests that high-dosage leptin treatment induces a state of partial leptin resistance. In aggregate, these studies establish the role of acute hypoleptinemia in regulating energy balance, the immune system, and reproductive function, and further suggest that high-dosage leptin treatment can induce a state of acquired leptin resistance.

Leptin-deficient (ob/ob) mice are resistant in different models of autoimmunity and inflammation, suggesting that leptin regulates immunity and inflammation. To investigate whether leptin deficiency modulates the spontaneous intestinal inflammation observed in interleukin (IL)-10-deficient mice, double IL-10- and leptin-deficient [IL-10 knockout (KO) ob/ob] mice were generated and compared with single IL-10 KO mice for colitis severity. Body weight in IL-10 KO ob/ob mice was significantly reduced compared with that of ob/ob mice. However, when compared with wild-type or IL-10 KO mice, IL-10 KO ob/ob mice were still markedly obese. IL-10 KO and IL-10 KO ob/ob mice developed colitis with a comparable time-course and severity in terms of macroscopic and histologic scores. Likewise, production of interferon-gamma, IL-6, and IL-13 from colon cultures and splenocytes did not differ among these two groups. Conversely, rates of apoptosis were higher in lamina propria lymphocytes obtained from the colon of IL-10 KO ob/ob compared with IL-10 KO mice. In conclusion, although leptin deficiency has been associated with resistance in models of autoimmunity and inflammation induced by exogenous stimuli, leptin appears not to play a significant role in the spontaneous colitis of IL-10 KO mice, although it modulates survival of intestinal lymphocytes.

It is known that, among human patients with sepsis, acute renal failure (ARF) dramatically increases mortality rates to 50 to 80%. However, the pathogenesis of septic ARF is not fully understood. An increase in endotoxin-induced mortality rates for leptin-deficient ob/ob mice was recently demonstrated. In comparison with ob/ob mice, db/db mice, which are deficient in the long isoforms of leptin receptors (Ob/Rb), demonstrate lower mortality rates after exposure to the endotoxin LPS. In db/db mice, mRNA for the short isoforms of leptin receptors is constitutively expressed in the kidney, lung, liver, and macrophages. It is known that plasma leptin levels increase in rodents after exposure to LPS, and this was demonstrated for db/db mice. Because ob/ob and db/db mice are both obese, factors other than obesity must be involved in the increased mortality rates for ob/ob mice. In this study, the hypothesis that the short forms of leptin receptors might offer protection against endotoxin-induced lethality at least in part by providing protection against ARF was examined. Serum leptin levels were significantly increased with LPS treatment in wild-type and db/db mice but not ob/ob mice. GFR decreased significantly 16 h after the homozygous ob/ob mice received intraperitoneal injections of 0.3 mg/kg LPS (0.37 +/- 0.04 ml/min per g kidney versus 0.83 +/- 0.06 ml/min per g kidney, n = 6, P < 0.01); the mean arterial pressure (MAP) remained unchanged. For ob/ob littermates (+/?ob), there was no significant change in either MAP or GFR when the mice were challenged with the same time interval (16 h) and dose of LPS. In contrast to ob/ob mice, there was no significant change in GFR or MAP when homozygous db/db mice or their littermates received injections of an even higher dose of LPS (0.4 mg/kg). Mouse recombinant leptin had no effect on GFR when ob/ob mice received 0.3 mg/kg LPS injections. However, renal function (serum creatinine levels, 0.4 +/- 0.1 mg/dl versus 0.9 +/- 0.1 mg/dl, P < 0.01) and MAP (68 +/- 4 mmHg versus 51 +/- 2 mmHg, n = 6, P < 0.01) were significantly improved with leptin replacement when the ob/ob mice developed hypotensive ARF with a higher dose of LPS (0.5 mg/kg). In summary, the previously reported increased susceptibility to LPS of ob/ob mice, compared with db/db mice, may be attributable at least in part to increased susceptibility to ARF.

Background & Aims: In addition to acting as a regulator of food intake and energy expenditure, leptin can also modulate immune and inflammatory responses. The role of leptin in intestinal inflammation is the focus of the present study., Methods: Acute and chronic colitis were induced in leptin-deficient ob/ob or wild-type (WT) mice using dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS). The severity of colitis was evaluated, and possible mechanisms were studied., Results: Leptin directly stimulates intraepithelial lymphocytes (IELs) and lamina propria mononuclear cells (LPMCs). In the DSS acute model, ob/ob mice exhibited a 72% reduction of colitis severity and spontaneous release of proinflammatory cytokines from the colon compared with WT mice. Replacement of leptin in ob/ob mice converted disease resistance to susceptibility, indicating that leptin deficiency, not obesity, accounts for the resistance to acute DSS-induced colitis. During chronic DSS-induced colitis and TNBS-induced colitis, in addition to reduced disease severity, ob/ob mice exhibited a significant attenuation in intestinal inflammation, accompanied by reduced production of cytokines and chemokines. When compared with WT mice, CD8(+) IELs of ob/ob mice were reduced in number as well as in their ability to synthesize interferon gamma. In addition, LPMCs of ob/ob mice showed increased apoptosis in untreated as well as DSS- or TNBS-treated mice. Phosphorylation of signal transducer and activator of transcription 3 and induction of cyclooxygenase 2 were absent in the colon of DSS-fed ob/ob mice., Conclusions: These results show that leptin represents a functional link between the endocrine and immune systems.

Leptin-deficient ob/ob mice are protected from Con A-induced hepatitis. However, it is unclear whether leptin deficiency or obesity itself is responsible for this protection. To address this question, wild-type (WT) obese mice with high serum leptin levels were generated by injection of gold thioglucose (WT GTG). Both Con A-injected WT and WT GTG mice developed hepatitis, whereas no hepatic damage was observed in ob/ob mice. Moreover, TNF-alpha and IFN-gamma levels as well as expression of the activation marker CD69 were elevated in liver mononuclear cells of WT and WT GTG mice, but not in ob/ob mice following administration of Con A. The liver of WT and WT GTG mice had the same percentage of NK T cells, a lymphocyte population involved in Con A-induced hepatitis. This population decreased equally in both WT and WT GTG mice after Con A injection. In contrast, the liver of ob/ob mice contained 50% less NK T cells compared to WT and WT GTG mice. Furthermore, no decrease in NK T cells was observed in Con A-injected ob/ob mice. We conclude that leptin-deficiency, not obesity, is responsible for protection from Con A-induced hepatitis.

Leptin, an appetite-regulating hormone/cytokine, circulates both free and bound to soluble leptin receptors (s-leptin R). An electrochemiluminescence (ECL) assay for the quantitative measurement of murine s-leptin R was developed. The absence of s-leptin R immunoreactivity in the serum of db(pas)/db(pas)mice demonstrated the specificity of the assay, which detected s-leptin R both in the free form and complexed with leptin. The distribution of free vs bound leptin and the regulation of s-leptin R were evaluated in mice following administration of the pro-inflammatory stimuli endotoxin (100 microg/mouse) and turpentine (100 microl/mouse). Both endotoxin and turpentine significantly increased serum leptin and s-leptin R levels compared to control mice. The distribution of free vs bound leptin was not altered by administration of endotoxin or turpentine. In fact, approximately 50% of total leptin was present in the free form in either control, endotoxin- or turpentine-injected mice. On the contrary, during the hyperleptinemia of pregnancy, only 10% of total leptin was present in the free form. We conclude that inflammation leads to the increase of both bound and free leptin. Therefore, the total amount of bioactive leptin is increased during acute inflammation, suggesting that leptin participates in the host response to inflammation., (Copyright 2001 Academic Press.)

Leptin, the product of the ob gene, is a pleiotropic molecule that regulates food intake as well as metabolic and endocrine functions. Leptin also plays a regulatory role in immunity, inflammation, and hematopoiesis. Alterations in immune and inflammatory responses are present in leptin- or leptin-receptor-deficient animals, as well as during starvation and malnutrition, two conditions characterized by low levels of circulating leptin. Both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines. Leptin exerts proliferative and antiapoptotic activities in a variety of cell types, including T lymphocytes, leukemia cells, and hematopoietic progenitors. Leptin also affects cytokine production, the activation of monocytes/macrophages, wound healing, angiogenesis, and hematopoiesis. Moreover, leptin production is acutely increased during infection and inflammation. This review focuses on the role of leptin in the modulation of the innate immune response, inflammation, and hematopoiesis.

The role of leptin was investigated in two models of T cell-mediated hepatitis: the administration of Con A or of Pseudomonas aeruginosa exotoxin A (PEA). In both models, leptin-deficient (ob/ob) mice were protected from liver damage and showed lower induction of tumor necrosis factor (TNF) alpha and IL-18 compared with their lean littermates. Neutralization of TNF-alpha reduced induction of IL-18 by either Con A (70% reduction) or PEA (40% reduction). Pretreatment of lean mice with either soluble TNF receptors or with an anti-IL-18 antiserum significantly reduced Con A- and PEA-induced liver damage. The simultaneous neutralization of TNF-alpha and IL-18 fully protected the mice against liver toxicity. However, neutralization of either IL-18 or TNF-alpha did not inhibit Con A-induced production of IFN-gamma. Thymus atrophy and alterations in the number of circulating lymphocytes and monocytes were observed in ob/ob mice. Exogenous leptin replacement restored the responsiveness of ob/ob mice to Con A and normalized their lymphocyte and monocyte populations. These results demonstrate that leptin deficiency leads to reduced production of TNF-alpha and IL-18 associated with reduced T cell-mediated hepatotoxicity. In addition, both TNF-alpha and IL-18 appear to be essential mediators of T cell-mediated liver injury.