White S.J.,Mayo Clinic Vaccine Research Group |
White S.J.,Mayo Medical School |
Taylor M.J.,Mayo Clinic Vaccine Research Group |
Taylor M.J.,Mayo Medical School |
And 4 more authors.
Vaccine | Year: 2013
Leptin is a pleiotropic hormone with multiple direct and regulatory immune functions. Leptin deficiency or resistance hinders the immunologic, metabolic, and neuroendocrinologic processes necessary to thwart infections and their associated complications, and to possibly protect against infectious diseases following vaccination. Circulating leptin levels are proportional to body fat mass. High circulating leptin concentrations, as observed in obesity, are indicative of the development of leptin transport saturation/signaling desensitization. Leptin bridges nutritional status and immunity. Although its role in vaccine response is currently unknown, over-nutrition has been shown to suppress vaccine-induced immune responses. For instance, obesity (BMI≥30kg/m2) is associated with lower antigen-specific antibody titers following influenza, hepatitis B, and tetanus vaccinations. This suggests that obesity, and possibly saturable leptin levels, are contributing factors to poor vaccine immunogenicity. While leptin-based therapies have not been investigated as vaccine adjuvants thus far, leptin's role in immunity suggests that application of these therapies is promising and worth investigation to enhance vaccine response in people with leptin signaling impairments. This review will examine the possibility of using leptin as a vaccine adjuvant by: briefly reviewing the distribution and signal transduction of leptin and its receptors; discussing the physiology of leptin with emphasis on its immune functions; reviewing the causes of attenuation of leptin signaling; and finally, providing plausible inferences for the innovative use of leptin-based pharmacotherapies as vaccine adjuvants. © 2013 Elsevier Ltd. Source
Singh P.,Mayo Medical School |
Peterson T.E.,Mayo Medical School |
Sert-Kuniyoshi F.H.,Mayo Medical School |
Glenn J.A.,Mayo Medical School |
And 5 more authors.
Circulation Research | Year: 2012
Rationale: The link between obesity, hyperleptinemia, and development of cardiovascular disease is not completely understood. Increases in leptin have been shown to impair leptin signaling via caveolin-1-dependent mechanisms. However, the role of hyperleptinemia versus impaired leptin signaling in adipose tissue is not known. Objective: To determine the presence and significance of leptin-dependent increases in adipose tissue caveolin-1 expression in humans. Methods and Results: We designed a longitudinal study to investigate the effects of increases in leptin on adipose tissue caveolin-1 expression during weight gain in humans. Ten volunteers underwent 8 weeks of overfeeding, during which they gained an average weight of 4.1±1.4 kg, with leptin increases from 7±3.8 to 12±5.7 ng/mL. Weight gain also resulted in changes in adipose tissue caveolin-1 expression, which correlated with increases in leptin (rho=0.79, P=0.01). In cultured human white preadipocytes, leptin increased caveolin-1 expression, which in turn impaired leptin cellular signaling. Functionally, leptin decreased lipid accumulation in differentiating human white preadipocytes, which was prevented by caveolin-1 overexpression. Further, leptin decreased perilipin and fatty acid synthase expression, which play an important role in lipid storage and biogenesis. Conclusions: In healthy humans, increases in leptin, as seen with modest weight gain, may increase caveolin-1 expression in adipose tissue. Increased caveolin-1 expression in turn impairs leptin signaling and attenuates leptin-dependent lowering of intracellular lipid accumulation. Our study suggests a leptin-dependent feedback mechanism that may be essential to facilitate adipocyte lipid storage during weight gain. © 2012 American Heart Association, Inc. Source
Singh P.,Mayo Medical School |
Sharma P.,Mayo Medical School |
Sahakyan K.R.,Mayo Medical School |
Davison D.E.,Mayo Medical School |
And 10 more authors.
International Journal of Obesity | Year: 2016
Adiponectin exerts beneficial effects by reducing inflammation and improving lipid metabolism and insulin sensitivity. Although the adiponectin level is lower in obese individuals, whether weight gain reduces adiponectin expression in humans is controversial. We sought to investigate the role of weight gain, and consequent changes in leptin, on altering adiponectin expression in humans.Methods/Results:Forty-four normal-weight healthy subjects were recruited (mean age 29 years; 14 women) and randomized to either gain 5% of body weight by 8 weeks of overfeeding (n=34) or maintain weight (n=10). Modest weight gain of 3.8±1.2 kg resulted in increased adiponectin level (P=0.03), whereas weight maintenance resulted in no changes in adiponectin. Further, changes in adiponectin correlated positively with changes in leptin (P=0.0085). In-vitro experiments using differentiated human white preadipocytes showed that leptin increased adiponectin mRNA and protein expression, whereas a leptin antagonist had opposite effects. To understand the role of leptin in established obesity, we compared adipose tissue samples obtained from normal-weight versus obese subjects. We noted, first, that leptin activated cellular signaling pathways and increased adiponectin mRNA in the adipose tissue from normal-weight participants, but did not do so in the adipose tissue from obese participants. Second, we noted that obese subjects had increased caveolin-1 expression, which attenuates leptin-dependent increases in adiponectin.Conclusions:Modest weight gain in healthy individuals is associated with increases in adiponectin levels, which correlate positively with changes in leptin. In vitro, leptin induces adiponectin expression, which is attenuated by increased caveolin-1 expression. In addition, the adipose tissue from obese subjects shows increased caveolin-1 expression and impaired leptin signaling. This leptin signal impairment may prevent concordant increases in adiponectin levels in obese subjects despite their high levels of leptin. Therefore, impaired leptin signaling may contribute to low adiponectin expression in obesity and may provide a target for increasing adiponectin expression, hence improving insulin sensitivity and cardio-metabolic profile in obesity. © 2016 Macmillan Publishers Limited. Source
Short K.R.,Endocrinology Research Unit |
Irving B.A.,Endocrinology Research Unit |
Basu A.,Endocrinology Research Unit |
Johnson C.M.,Mayo Medical School |
And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012
Context: Type 2 diabetes (T2D) is characterized by insulin resistance to glucose metabolism. Most studies suggest that protein metabolism is unaffected by T2D, but regional protein metabolism and response to multiple doses of insulin have not been examined. Objective: Our objective was to determine whether insulin regulation of splanchnic and leg protein metabolism are affected by T2D during hyperglycemia and graded insulin levels. Design and Setting: We conducted a cross-sectional study at an academic medical center. Participants: T2D and non-T2D adults were matched for age (62 yr) and body mass index (30 kg/m2). Interventions: Glucose was maintained at approximately 9 mmol/liter while insulin was infused at three progressively higher rates, achieving circulating concentrations of approximately 150, 350, and 700 pmol/liter, respectively. Main Outcome Measures: Protein kinetics were measured using labeled phenylalanine (Phe) and tyrosine (Tyr). Results: Whole-body protein breakdown and synthesis rates were higher in T2D but declined with increasing insulin in both groups. Leg Phe and Tyr appearance and disappearance and estimates of protein breakdown and synthesis, respectively, were higher in T2D but did not decline significantly with insulin, resulting in similar net balance between groups. Splanchnic response to insulin was blunted in T2D, shown by a smaller reduction in rates of disappearance and net balance of Phe and Tyr as insulin increased. Splanchnic conversion of Phe to Tyr was lower in T2D and less sensitive to insulin, whereas nonsplanchnic Phe to Tyr tended to be higher in T2D. Conclusions: T2D results in higher whole-body, splanchnic, and leg protein turnover and blunts the insulin-mediated suppression of splanchnic protein anabolism under hyperglycemic, hyperinsulinemic conditions. Copyright © 2012 by The Endocrine Society. Source
Gao J.J.,University of Missouri - Kansas City |
Shen J.,University of Missouri - Kansas City |
Kolbert C.,Endocrinology Research Unit |
Raghavakaimal S.,Endocrinology Research Unit |
And 5 more authors.
Shock | Year: 2010
Our previous work has provided strong evidence that the proteasome is central to most of the genes induced in mouse macrophages in response to LPS stimulation. In the studies presented here, we evaluated the role of the macrophage proteasome in response to a second microbial product CpG DNA (unmethylated bacterial DNA). For these studies, we applied Affymetrix microarray analysis of RNA derived from murine macrophages stimulated with CpG DNA in the presence or absence of proteasome inhibitor, lactacystin. The results of these studies revealed that similar to LPS, most of those macrophage genes regulated by CpG DNA are also under the control of the proteasome at 4 h. In contrast to LPS stimulation, however, many of these genes were induced much later than 4 h, at 18 h, in response to CpG DNA. Lactacystin treatment of macrophages completely blocked the CpG DNA-induced gene expression of TNF-α and other genes involved in the production of inflammatory mediators. These data strongly support the conclusion that similar to LPS, the macrophage proteasome is a key regulator of CpG DNA-induced signaling pathways. © 2010 by the Shock Society. Source