Papers by Sebastian Parlee
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Maternal low-protein diet (LP) throughout gestation affects pancreatic β-cell fraction of the off... more Maternal low-protein diet (LP) throughout gestation affects pancreatic β-cell fraction of the offspring at birth, thus increasing their susceptibility to metabolic dysfunction and type 2 diabetes in adulthood. The present study sought to strictly examine the effects of LP during the last week of gestation (LP12.5) alone as a developmental window for β-cell programming and metabolic dysfunction in adulthood. Islet morphology analysis revealed normal β-cell fraction in LP12.5 newborns. Normal glucose tolerance was observed in 6- to 8-wk-old male and female LP12.5 offspring. However, male LP12.5 offspring displayed glucose intolerance and reduced insulin sensitivity associated with β-cell dysfunction with aging. High-fat diet exposure of metabolically normal 12-wk-old male LP12.5 induced glucose intolerance due to increased body weight, insulin resistance, and insufficient β-cell mass adaptation despite higher insulin secretion. Assessment of epigenetic mechanisms through microRNAs (mi...
ACS Pharmacology & Translational Science
Molecular metabolism, Jan 11, 2018
To signal, FGF19 and FGF21 require co-receptor βKlotho (KLB) to act in concert with FGF receptors... more To signal, FGF19 and FGF21 require co-receptor βKlotho (KLB) to act in concert with FGF receptors, and yet there is appreciable variance in the C-terminal sequences of these two novel metabolic hormones where binding is believed to be primary. We seek to determine the functional consequences for these amino acid differences and determine whether such information can be used to design high potency antagonists and agonists. We employed a functional in vitro assay to identify C-terminal protein fragments capable of fully blocking KLB-mediated FGF19 and 21 receptor signaling. The key residues in each hormone responsible for support full bioactivity were identified through peptide-based Ala-scanning. Chemical optimization of the peptides was employed to increase their antagonistic potency. An optimized sequence as a substituted part of a full length FGF21 was assessed for enhanced FGFR/KLB-mediated agonism using tissue culture and obese mice. C-terminal FGF19 and FGF21 peptides of relati...
Bone, Jan 19, 2018
Bone marrow adipose tissue (BMAT) is preserved or increased in states of caloric restriction. Sim... more Bone marrow adipose tissue (BMAT) is preserved or increased in states of caloric restriction. Similarly, we found that BMAT in the tail vertebrae, but not the red marrow in the tibia, resists loss of neutral lipid with acute, 48-hour fasting in rats. The mechanisms underlying this phenomenon and its seemingly distinct regulation from peripheral white adipose tissue (WAT) remain unknown. To test the role of β-adrenergic stimulation, a major regulator of adipose tissue lipolysis, we examined the responses of BMAT to β-adrenergic agonists. Relative to inguinal WAT, BMAT had reduced phosphorylation of hormone sensitive lipase (HSL) after treatment with pan-β-adrenergic agonist isoproterenol. Phosphorylation of HSL in response to β3-adrenergic agonist CL316,243 was decreased by an additional ~90% (distal tibia BMAT) or could not be detected (tail vertebrae). Ex vivo, adrenergic stimulation of lipolysis in purified BMAT adipocytes was also substantially less than iWAT adipocytes and had s...
Obesity surgery, Dec 29, 2017
Obesity-associated systemic hypertension (HTN) and obstructive sleep apnea (OSA) have multiple pa... more Obesity-associated systemic hypertension (HTN) and obstructive sleep apnea (OSA) have multiple pathophysiological pathways including ectopic fat deposition, inflammation, altered adipokine profile, and increased sympathetic nervous activity. We characterized these potential mechanisms in severely obese patients with or without HTN and OSA. We also compared changes of these mechanisms at 12 months following biliopancreatic diversion with duodenal switch (BPD-DS) surgery according to HTN and OSA resolution. Sixty-two severely obese patients were evaluated at baseline and 12 months; 40 patients underwent BPD-DS. Blood samples, bioelectrical impedance analysis, computed tomography scan, and 24-h heart rate monitoring were performed. OSA have been determined with polysomnography and HTN with blood pressure measurement and medical file. Patients with HTN (n = 35) and OSA (n = 32) were older men with higher ectopic fat deposition and lower parasympathetic nervous activity without differenc...
Diabetes, Obesity and Metabolism, 2017
Endocrine Connections, 2016
Prochemerin is the inactive precursor of the adipokine chemerin. Proteolytic processing is obliga... more Prochemerin is the inactive precursor of the adipokine chemerin. Proteolytic processing is obligatory for the conversion of prochemerin into active chemerin and subsequent regulation of cellular processes via the chemokine-like receptor 1 (CMKLR1). Elevated plasma or serum chemerin concentrations and differential processing of prochemerin have been reported in obese humans. The impact of these changes on CMKLR1 signalling in humans is unknown. The objective of this pilot study was to develop a cellular bioassay to measure CMKLR1 activation by chemerin present in human serum and to characterise how obesity modifies serum activation of CMKLR1 under fasted and fed conditions. Blood samples were collected from control (N = 4, BMI 20–25) and obese (N = 4, BMI >30) female subjects after an overnight fast (n = 2) and at regular intervals (n = 7) following consumption of breakfast over a period of 6 h. A cellular CMKLR1-luminescent reporter assay and a pan-chemerin ELISA were used to det...
Analytical and bioanalytical chemistry, Jan 19, 2016
Microfluidics is an enabling technology for both cell biology and chemical analysis. We combine t... more Microfluidics is an enabling technology for both cell biology and chemical analysis. We combine these attributes with a microfluidic device for on-line solid-phase extraction (SPE) and mass spectrometry (MS) analysis of secreted metabolites from living cells in culture on the chip. The device was constructed with polydimethylsiloxane (PDMS) and contains a reversibly sealed chamber for perfusing cells. A multilayer design allowed a series of valves to control an on-chip 7.5 μL injection loop downstream of the cell chamber with operation similar to a six-port valve. The valve collects sample and then diverts it to a packed SPE bed that was connected in-line to treat samples prior to MS analysis. The valve allows samples to be collected and injected onto the SPE bed while preventing exposure of cells to added back pressure from the SPE bed and organic solvents needed to elute collected chemicals. Here, cultured murine 3T3-L1 adipocytes were loaded into the cell chamber and non-esterifi...
Frontiers in Endocrinology, 2016
The Faseb Journal, Mar 1, 2008
The Faseb Journal, Apr 1, 2009
Endocrinology, Jan 22, 2015
Bone marrow adipose tissue (MAT) accounts for up to 70% of bone marrow volume in healthy adults a... more Bone marrow adipose tissue (MAT) accounts for up to 70% of bone marrow volume in healthy adults and increases further in clinical conditions of altered skeletal or metabolic function. Perhaps most strikingly, and in stark contrast to white adipose tissue (WAT), MAT has been found to increase during caloric restriction (CR) in humans and many other species. Hypoleptinemia may drive MAT expansion during CR but this has not been demonstrated conclusively. Indeed, MAT formation and function are poorly understood; hence, the physiological and pathological roles of MAT remain elusive. We recently revealed that MAT contributes to hyperadiponectinemia and systemic adaptations to CR. To further these observations, we have now performed CR studies in rabbits to determine if CR affects adiponectin production by MAT. Moderate or extensive CR decreased bone mass, WAT mass, and circulating leptin, but, surprisingly, did not cause hyperadiponectinemia or MAT expansion. Although this unexpected fin...
Obesity (Silver Spring, Md.), 2015
Bariatric surgery remains the most effective treatment for obesity and metabolic syndrome. Surgic... more Bariatric surgery remains the most effective treatment for obesity and metabolic syndrome. Surgical benefit arises from early-phase resolution of hyperglycemia and late-phase weight loss. The adipokine chemerin is of interest given its roles in immunity, adipogenesis, and metabolism. The study objective was to examine the effects of biliopancreatic diversion with duodenal switch (BPD-DS) on plasma chemerin in the early and late post-operative stages. 83 adults with obesity undergoing BPD-DS, 45 obese non-surgical controls, and 9 lean surgical controls were enrolled. Plasma parameters and anthropometric measures were obtained at baseline and at, early (24 h, 5 D) and late (6 months and 12 months) post-operative stages. Plasma chemerin dropped from 176±49 ng/mL at baseline to 132±52 ng/mL 24 h after BPD-DS, rebounded to 200±66 ng/mL after 5 D, and declined to 124±51 and 110±34 ng/mL after 6 and 12 months. Plasma chemerin correlated negatively with measures of inflammation and hepatic ...
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Papers by Sebastian Parlee