Excessive Lipolysis Research Articles

Metabolic dysfunction in obstructive sleep apnea: A critical examination of underlying mechanisms.

It has recently become clear that obstructive sleep apnea (OSA) is an independent risk factor for the development of metabolic syndrome, a disorder of defective energy storage and use. Several mechanisms have been proposed to explain this finding, drawing upon the characteristics that define OSA. In particular, intermittent hypoxia, sleep fragmentation, elevated sympathetic tone, and oxidative stress - all consequences of OSA - have been implicated in the progression of poor metabolic outcomes in OSA. In this review we examine the evidence to support each of these disease manifestations of OSA as a unique risk for metabolic dysfunction. Tissue hypoxia and sleep fragmentation are each directly connected to insulin resistance and hypertension, and each of these also may increase sympathetic tone, resulting in defective glucose homeostasis, excessive lipolysis, and elevated blood pressure. Oxidative stress further worsens insulin resistance and in turn, metabolic dysfunction also increases oxidative stress. However, despite many studies linking each of these individual components of OSA to the development of metabolic syndrome, there are very few reports that actually provide a coherent narrative about the mechanism underlying metabolic dysfunction in OSA.

Additive effects of β-adrenergic and cytokine signaling on lipolytic activation

Obesity often leads to increased systemic inflammation which is now thought to play a causative role in the development of atherosclerotic disease and insulin resistance. This inflammatory response originates within large adipose tissue depots and is initiated by classically activated macrophages that infiltrate the tissue from the circulation. The large number of macrophages residing in obese adipose tissue leads to significant increases in interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) secretion; achieving levels sufficient to elevate circulating plasma concentrations. These cytokines activate potent signals to initiate lipolysis, to release free fatty acids from triacylglycerol stores and contribute to hyperlipidemia in obese individuals. Obese adipose tissue responds to normal β-adrenergic and glucagon stimuli to recover from negative energy balance by inducing lipolysis. However, it is not clear what quantitative influence additional lipolytic stimulation by IL-6 and TNFα has on normal β-adrenergic activity. Although, β-adrenergic and cytokine signaling activate separate pathways for lipolytic activation, it is undefined whether the effects of multiple signaling events on lipolysis are additive or coincident. To clarify this issue, we measured lipolytic activity in 3T3-L1-derived adipocytes stimulated by a β-adrenergic agonist (isoproterenol), IL-6 or TNFα individually and in combinations as co- and tri-stimulation. Treatment of adipocytes with isoproterenol and either IL-6 or TNFα as co-stimulants increased lipolytic activation by approximately the sum of the individual ligands, suggesting contributions from two independent pathways. Co-stimulation with IL-6 and TNFα provided slightly more than an additive response indicating signaling contributions from independent and common pathways. Tri-stimulation resulted in the largest level of lipolytic activation with a value approximate to adding isoproterenol stimulation to a combined treatment of IL-6 and TNFα. The additive nature of cytokine signaling to β-adrenergic activity suggests its therapeutic inhibition will prevent excessive lipolysis, yet minimally interfere with maintaining normal responses to varying energy demands.

Nonalcoholic fatty pancreatic disease and cardio-metabolic risk: is there is a place for obstructive sleep apnea?

BackgroundObstructive sleep apnea is a common disorder acting as a risk factor for the development and progression of cardiometabolic derangements including non-alcoholic fatty liver disease. Recent research data suggest that non-alcoholic fatty pancreatic disease may be a more sensitive marker than non-alcoholic fatty liver disease for early subclinical metabolic risk and may contribute to the progression of subclinical disease to overt type 2 diabetes mellitus.Presentation of the hypothesisWe postulate that obstructive sleep apnea may be a risk factor for non-alcoholic fatty pancreatic disease. It is well known that intermittent hypoxia related to obstructive sleep apnea leads to hormonal derangements. Excessive lipolysis, enhanced lipid synthesis and systemic and local inflammation may favor ectopic fat deposition similarly to non-alcoholic fatty liver disease. Furthermore, it is possible that obstructive sleep apnea can lead to pancreatic beta cell damage via intermittent hypoxia.Testing of the hypothesisFuture research should focus on the following: first, whether non-alcoholic fatty pancreatic disease is an independent risk factor for the development of metabolic disease including diabetes mellitus or is a simple consequence of obesity; second, the prevalence of non-alcoholic fatty pancreatic disease among people with obstructive sleep apnea and vice versa, which should be compared to the prevalence of these diseases in general population; third, whether coexistence of these conditions is related to greater cardiometabolic risk than either disease alone; and fourth, whether the treatment of obstructive sleep apnea will translate into the resolution of non-alcoholic fatty pancreatic disease.Implications of the hypothesisIf proven, this hypothesis will provide new knowledge on the complex interplay between various metabolic insults. Second, screening for NAFPD may identify individuals at risk for developing type 2 diabetes mellitus for targeted prevention. Third, screening for the presence of non-alcoholic fatty pancreatic disease in patients with obstructive sleep apnea may help to decrease the incidence of diabetes mellitus through a targeted prevention.

내냉성 미생물인 Acinetobacter genomospecies 10과 Serratia liquefaciens가 원유의 품질에 미치는 영향

살균한 원유에 지방분해효소와 단백질 분해효소활성이 가장 높게 나타났던 균주를 접종하고 저장하면서 내냉성미생물이 생성하는 효소가 원유의 품질에 미치는 영향을 조사하였다. 지방분해효소활성이 높은 Acinetobacter genomospecies 10은 냉장저장기간 중 총 고형분과 유지방의 함량에 영향을 미치지 않았고, 지방의 분해는 냉장보관 14일째에 대조구와 비교하여 2.6배 이상의 유리지방산을 생성하였다. 생성된 지방산의 조성은 short chain free fatty acid(SCFFA), middle chain free fatty acid(MCFFA) 및 long chain free fatty acid(LCFFA)를 모두 생성하였으며, 특히 SCFFA와 MCFFA의 증가율이 높았다. 단백질 분해효소활성이 높은 Serratia liquefaciens은 원유의 총 고형분과 유단백질 함량에 영향을 미치지 않았고, 단백질 조성의 변화는 냉장저장기간 동안 케이신의 함량이 서서히 감소하다가 10일째부터 <TEX>$\kappa$</TEX>-케이신의 함량이 현저히 감소하였다. 유리아미노산은 대조구와 비교하여 냉장저장 14일째 2.8배 이상 생성되었으며 특히 소수성 아미노산으로 쓴맛을 내는 leucin, valine 등의 함량이 급격히 증가하였다. This study was conducted to investigate effect of psychrotrophic bacteria on the quality of raw milk. Acinetobacter genomospecies 10 was selected as lipolytic species, and Serratia liquefaciens as proteolytic species. Lipase present in inoculated raw milk with Acinetobacter genomospecies 10 did not affect total solid and fat contents. However, the free fatty acid (FFA) content, especially short chain FFAs, of milk with Acinetobacter genomospecies 10 was dramatically increased. FFAs produced by lipolysis of milk fat are important in flavor of dairy products, excessive lipolysis occurring in milk and dairy products could cause off-flavor, and produced FFAs may have an underiable effect on their flavor. In addition, protease influenced the quality of inoculated raw milk with Serratia liquefaciens. In degradation patterns of casein by SDS-PAGE analysis from inoculatred raw milk with Serratia liquefaciens, casein content was gradually decreased during storage at <TEX>$4^{\circ}C$</TEX>, and extensive degradation of <TEX>$\kappa$</TEX>-casein was observed on the storage day of 13. The free amino acids such as leucine, valine, arginine, and tyrosine were dramatically increased, which causes bitter taste in raw milk. These excessive peptides in dairy products, produced by psychrotrophic bacteria, can be possible to develop off-flavors and be responsible for gelling of milk by degradation.

Changing characteristics of the type 2 diabetes epidemic of China and other Asian countries.

Changing characteristics of the type 2 diabetes epidemic of China and other Asian countries.

Preeclampsia Is Associated With Compromised Maternal Synthesis of Long-Chain Polyunsaturated Fatty Acids, Leading to Offspring Deficiency

Obesity and excessive lipolysis are implicated in preeclampsia (PE). Intrauterine growth restriction is associated with low maternal body mass index and decreased lipolysis. Our aim was to assess how maternal and offspring fatty acid metabolism is altered in mothers in the third trimester of pregnancy with PE (n=62) or intrauterine growth restriction (n=23) compared with healthy pregnancies (n=164). Markers of lipid metabolism and erythrocyte fatty acid concentrations were measured. Maternal adipose tissue fatty acid composition and mRNA expression of adipose tissue fatty acid–metabolizing enzymes and placental fatty acid transporters were compared. Mothers with PE had higher plasma triglyceride (21%, P &lt;0.001) and nonesterified fatty acid (50%, P &lt;0.001) concentrations than controls. Concentrations of major n−6 and n−3 long-chain polyunsaturated fatty acids in erythrocytes were 23% to 60% lower (all P &lt;0.005) in PE and intrauterine growth restriction mothers and offspring compared with controls. Subcutaneous adipose tissue Δ−5 and Δ−6 desaturase and very long-chain fatty acid elongase mRNA expression was lower in PE than controls (respectively, mean [SD] control 3.38 [2.96] versus PE 1.83 [1.91], P =0.030; 3.33 [2.25] versus 1.03 [0.96], P &lt;0.001; 0.40 [0.81] versus 0.00 [0.00], P =0.038 expression relative to control gene [square root]). Low maternal and fetal long-chain polyunsaturated fatty acid concentrations in PE may be the result of decreased maternal synthesis.

Glucocorticoids antagonize tumor necrosis factor-α-stimulated lipolysis and resistance to the antilipolytic effect of insulin in human adipocytes

High concentrations of TNF within obese adipose tissue increase basal lipolysis and antagonize insulin signaling. Adipocytes of the obese are also exposed to elevated levels of glucocorticoids (GCs), which antagonize TNF actions in many cell types. We tested the hypothesis that TNF decreases sensitivity to the antilipolytic effect of insulin and that GCs antagonize this effect in differentiated human adipocytes. Lipolysis and expression levels of lipolytic proteins were measured after treating adipocytes with TNF, dexamethasone (DEX), or DEX + TNF for up to 48 h. TNF not only increased basal lipolysis, it caused resistance to the antilipolytic effects of insulin in human adipocytes. DEX alone did not significantly affect lipolysis. Cotreatment with DEX blocked TNF induction of basal lipolysis and insulin resistance by antagonizing TNF stimulation of PKA-mediated phosphorylation of hormone-sensitive lipase (HSL) at Ser⁵⁶³ and Ser⁶⁶⁰ and perilipin. TNF did not affect perilipin, HSL, or phosphodiesterase-3B mass but paradoxically suppressed adipose tissue triglyceride lipase expression, and this effect was blocked by DEX. The extent to which GCs can restrain the lipolytic actions of TNF may both diminish the potentially deleterious effects of excess lipolysis and contribute to fat accumulation in obesity.

Role of peroxisome proliferator-activated receptor gamma agonist in improving hepatic steatosis: Possible molecular mechanism.

Role of peroxisome proliferator-activated receptor gamma agonist in improving hepatic steatosis: Possible molecular mechanism.

The need for co-ordinated studies for obesity-related problems like diabetes mellitus in Libyan population

Obesity is one of the major risk factors of type 2 diabetes and is associated with many metabolic derangements that impair insulin sensitivity. These abnormalities include excess lipolysis causing increased concentrations of non-esterified fatty acids and triglycerides in blood and skeletal muscle. Muscle glucose uptake is suppressed. (Published: 22 March 2012) Citation: Libyan J Med 2012, 7 : 17314 - DOI: 10.3402/ljm.v7i0.17314

Regulation of fat specific protein 27 by isoproterenol and TNF-α to control lipolysis in murine adipocytes

The lipid droplet-associated fat specific protein 27 (FSP27) suppresses lipolysis and thereby enhances triglyceride accumulation in adipocytes. We and others have recently found FSP27 to be a remarkably short-lived protein (half-life, 15 min) due to its rapid ubiquitination and proteasomal degradation. Thus, we tested the hypothesis that lipolytic agents such as tumor necrosis factor-α (TNF-α) and isoproterenol modulate FSP27 levels to regulate FFA release. Consistent with this concept, we showed that the lipolytic actions of TNF-α, interleukin-1β (IL-1β), and IFN-γ are accompanied by marked decreases in FSP27 expression and lipid droplet size in mouse adipocytes. Similar depletion of FSP27 using short interfering RNA (siRNA) mimicked the lipolysis-enhancing effect of TNF-α, while maintaining stable FSP27 levels using expression of hemagglutinin epitope-tagged FSP27 blocked TNF-α-mediated lipolysis. In contrast, we show the robust lipolytic action of isoproterenol is paradoxically associated with increases in FSP27 levels and a delayed degradation rate corresponding to decreased ubiquitination. This catecholamine-mediated increase in FSP27 abundance, probably a feedback mechanism for restraining excessive lipolysis by catecholamines, is mimicked by forskolin or 8-bromo-cAMP treatment and is prevented by the protein kinase A (PKA) inhibitor KT5720 or by PKA depletion using siRNA. Taken together, these data identify the regulation of FSP27 as an important intermediate in the mechanism of lipolysis in adipocytes in response to TNF-α and isoproterenol.

Diabetes as a Paracrinopathy of the Islets of Langerhans

The small clusters of cells scattered in the pancreas and discovered by Langerhans in 1869, currently known as the islets of Langerhans, are at the centre of the pathology of diabetes. Today they appear as sophisticated micro-organs in which various cell types function in a remarkably co-ordinated manner. Until recently, most of the interest has been centred on the β-cells, which synthesise, store and secrete insulin. Insulin deficiency is the hallmark of diabetes, with insulin resistance being associated with some forms of the disease. Although identified more than 40 years ago, a possible role of glucagon in the pathophysiology of diabetes has been largely neglected. Synthesised, stored and released by the α-cells of the islets of Langerhans, glucagon plays a key role in the main metabolic disturbances of diabetes that are hyperglycaemia and excessive lipolysis and ketogenesis. Suggested by Samols et al. decades ago, the possibility of close interactions between α- and β-cells within the islets of Langerhans has recently received considerable experimental support. Unger and Orci have proposed that such paracrine interactions within the pancreatic islets play a crucial role in a vital homoeostatic domain and that disruption or dysfunction of these interactions has to be considered as a key component in the pathophysiology of diabetes. This brief article will present arguments supporting the view of diabetes as a paracrinopathy of the islets of Langerhans.

Measurement of myocardial triglyceride content by magnetic resonance spectroscopy in transplant native heart autopsies

Introduction Cardiac dysfunction has been associated with excessive myocardial lipolysis in animal models. Measurements of myocardial triglycerides in humans have been performed using proton MR spectroscopy (1H-MRS) [1,2]. The measured volume is usually selected within the ventricular septum to avoid the contamination from epicardial fat and to eliminate the artifacts from cardiac motion. It is difficult to assess the spatial distribution of the fat deposition in human myocardium by 1H-MRS. Hence, whether the fat content within the septum can be generalized to represent the whole cardiac tissue remains unknown.

High lipolytic activity and dyslipidemia in a Spontaneous Hypertensive/NIH Corpulent (SHR/N-cp) rat: a genetic model of obesity and type 2 diabetes mellitus

In order to better understand the link between obesity and type 2 diabetes, lipolysis and its adrenergic regulation was investigated in various adipose depots of obese adult females SHR/N-cp rats. Serum insulin, glucose, free fatty acids (FFA), triglycerides (TG) and glycerol were measured. Adipocytes were isolated from subcutaneous (SC), parametrial (PM) and retroperitoneal (RP) fat pads. Total cell number and size, basal lipolysis or stimulated by norepinephrine (NE) and BRL 37344 were measured in each depot. Obese rats were hyperinsulinemic and hyperglycemic, suggesting high insulin resistance. They presented a marked dyslipidemia, attested by increased serum FFA and TG levels. High serum glycerol levels also suggest a strong lipolytic rate. Obese rats showed an excessive development of all fat pads although a more pronounced effect was observed in the SC one. The cellularity of this depot was increased 8 fold when compared to lean rats, but these fat cells were only 1.5 to 2-fold larger. SC adipocytes showed a marked increase in their basal lipolytic activity but a lack of change in responsiveness to NE or BRL 37344. The association between high basal lipolysis and increased cellularity yields to a marked adipose cell lipolytic rate, especially from the SC region. SHR/N-cp rats were characterized by a hyperplasic type of obesity with an excessive development of the SC depot. The dyslipidemia, attested by an altered serum lipid profile could be attributed to excessive lipolysis that contributes to increased FFA levels, and to early development of insulin resistance through a lipotoxicity effect.

Adipose tissue–skeletal muscle crosstalk: are endocannabinoids an unwanted caller?

Adipose tissue was historically regarded as an inert depot for triacylglycerol storage; however, it is now recognised as a major endocrine organ that is central to whole-body metabolic homeostasis. The adipocyte exerts its effects on lipid and carbohydrate use by producing and releasing peptides/hormones that signal to other tissues to convey biological signals. Indeed, the concept of metabolic ‘crosstalk’ between adipose tissue and other key organs that regulate metabolism is the subject of much research. Obesity is characterised by adipocyte hypertrophy, an expanded visceral and subcutaneous adipose tissue mass and altered cellular biology [1]. While obesity is undoubtedly a major risk factor for insulin resistance, the factors linking these pathologies are not well defined. Currently, there are two prevailing views to explain this link. The lipocentric view is that excessive lipolysis in an expanded adipose tissue mass results in an oversupply of NEFA to peripheral metabolic tissues that are not equipped to store excess lipids. The resulting ectopic lipid deposition activates serine/ threonine kinases (i.e. c-Jun N-terminal kinase [JNK], inhibitor of κB kinase, conventional protein kinase C) that directly disrupt insulin signal transduction [2]. In severe cases, ectopic lipid accumulation induces lipotoxic cell death [3]. An alternative view is that obesity generates a chronic low-grade inflammatory response. This is characterised by abnormal cytokine production (e.g. TNFα, IL-6), mostly in adipocytes, but also in macrophages that are recruited to, and reside in, adipose tissue. These, in turn, activate the aforementioned serine/threonine kinases in metabolic tissues to inhibit insulin action [4]. The likelihood is that both mediators, and others, contribute to insulin resistance in human obesity. In this issue of Diabetologia, Eckardt and colleagues [5] have provided new evidence that the endocannabinoid system (ECS) is directly involved in the negative crosstalk between adipose tissue and skeletal muscle, thereby adding endocannabinoids to the growing list of adipocyte-derived factors that mediate skeletal muscle insulin resistance. Endocannabinoids are a family of lipid ligands derived from cell membrane phospholipids that bind and activate the type 1 and type 2 cannabinoid receptors (CB1R and CB2R), encoded by CNR1 and CNR2, respectively. Stimulation of the endocannabinoid system, mainly via CB1R, increases food intake, promotes weight gain, induces lipogenesis in liver and adipose tissue and causes whole body glucose intolerance [6]. The ECS is overactivated in obesity [7], and studies in Cnr1 mice reveal a lean phenotype that is resistant to diet-induced obesity [8]. Although endocannabinoids are implicated in the development of obesity through central and peripheral mechanisms, the tissue-specific contribution of the ECS to metabolic regulation, particularly in skeletal muscle, is incompletely described. Diabetologia (2009) 52:571–573 DOI 10.1007/s00125-009-1287-x

The Neuroendocrine Effects of Traumatic Brain Injury

The Neuroendocrine Effects of Traumatic Brain Injury

The Neuroendocrine Effects of Traumatic Brain Injury

Neuroendocrine dysfunction after traumatic brain injury (TBI) is under-diagnosed, under-treated, and may adversely affect the rate of recovery. Single or multiple pituitary-target hormone disruption occurs in up to two-thirds of persons with TBI, most commonly affecting the gonadal and growth hormone axes. The time course of decline in and recovery of pituitary function in relation to cognitive dysfunction and rehabilitation progress are not well described. This article reviews the clinical spectrum of neuroendocrine deficits after TBI and their underlying mechanisms. Future studies of the effects of hormonal replacement on recovery are recommended.

Obesity and Atherogenic Dyslipidemia

Obesity is associated with an increased risk of coronary heart disease, in part due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol. There has been substantial research effort focused on the mechanisms of the link between obesity and atherogenic dyslipidemia, both in the absence and presence of insulin resistance. After a brief overview of the epidemiology of atherogenic dyslipidemia, this article details the known molecular mechanisms of adipocyte function and its relationship to apoB-containing lipoprotein assembly and metabolism, both in the healthy as well as in the obese states. We also discuss the pathophysiology of low HDL cholesterol in obesity and the implications for cardiovascular disease risk.

Influence of composition on the biochemical and sensory characteristics of commercial Cheddar cheese of variable quality and fat content

Ten commercial Cheddar cheeses of variable quality differing in fat content and age were subjected to compositional, proteolytic, lipolytic and sensory analyses. The compositional parameters of the full‐fat cheeses were predominantly outside those typically associated with good‐quality cheese. Sensory analysis discriminated the full‐fat cheeses predominantly by age, with the longer ripened cheeses associated with more negative attributes, some which appeared to be due to excessive lipolysis and/or β‐casein breakdown. Both proteolysis and lipolysis appear to be age dependent. The two reduced‐fat cheeses were clearly discriminated from the eight full‐fat cheeses by sensory analysis that appeared to be due to differences in composition and the extent of lipolysis.

Thematic review series: Patient-Oriented Research. Free fatty acid metabolism in human obesity

Adipose tissue lipolysis provides circulating FFAs to meet the body's lipid fuel demands. FFA release is well regulated in normal-weight individuals; however, in upper-body obesity, excess lipolysis is commonly seen. This abnormality is considered a cause for at least some of the metabolic defects (dyslipidemia, insulin resistance) associated with upper-body obesity. "Normal" lipolysis is sex-specific and largely determined by the individual's resting metabolic rate. Women have greater FFA release rates than men without higher FFA concentrations or greater fatty acid oxidation, indicating that they have greater nonoxidative FFA disposal, although the processes and tissues involved in this phenomenon are unknown. Therefore, women have the advantage of having greater FFA availability without exposing their tissues to higher and potentially harmful FFA concentrations. Upper-body fat is more lipolytically active than lower-body fat in both women and men. FFA released by the visceral fat depot contributes only a small percentage of systemic FFA delivery. Upper-body subcutaneous fat is the dominant contributor to circulating FFAs and the source of the excess FFA release in upper-body obesity. We believe that abnormalities in subcutaneous lipolysis could be more important than those in visceral lipolysis as a cause of peripheral insulin resistance. Understanding the regulation of FFA availability will help to discover new approaches to treat FFA-induced abnormalities in obesity.

CD36 deficiency in mice impairs lipoprotein lipase-mediated triglyceride clearance

CD36 is involved in high-affinity peripheral FFA uptake. CD36-deficient (cd36(-)(/)(-)) mice exhibit increased plasma FFA and triglyceride (TG) levels. The aim of the present study was to elucidate the cause of the increased plasma TG levels in cd36(-)(/)(-) mice. cd36(-)(/)(-) mice showed no differences in hepatic VLDL-TG production or intestinal [(3)H]TG uptake compared with wild-type littermates. cd36(-)(/)(-) mice showed a 2-fold enhanced postprandial TG response upon an intragastric fat load (P < 0.05), with a concomitant 2.5-fold increased FFA response (P < 0.05), suggesting that the increased FFA in cd36(-/-) mice may impair LPL-mediated TG hydrolysis. Postheparin LPL levels were not affected. However, the in vitro LPL-mediated TG hydrolysis rate as induced by postheparin plasma of cd36(-)(/)(-) mice in the absence of excess FFA-free BSA was reduced 2-fold compared with wild-type plasma (P < 0.05). This inhibition was relieved upon the addition of excess FFA-free BSA. Likewise, increasing plasma FFA in wild-type mice to the levels observed in cd36(-)(/)(-) mice by infusion prolonged the plasma half-life of glycerol tri[(3)H]oleate-labeled VLDL-like emulsion particles by 2.5-fold (P < 0.05). We conclude that the increased plasma TG levels observed in cd36(-)(/)(-) mice are caused by decreased LPL-mediated hydrolysis of TG-rich lipoproteins resulting from FFA-induced product inhibition of LPL.