Decrease In Lipolysis Research Articles

Design, evaluation, and in vitro-in vivo correlation of self-nanoemulsifying drug delivery systems to improve the oral absorption of exenatide.

The ability to predict the absorption of exenatide (Ex), a GLP-1 analogue, after oral dosing to rats in self-nanoemulsifying drug delivery systems (SNEDDS), using in vitro methods, was assessed. Ex was complexed with soybean phosphatidylcholine (SPC) prior to loading into SNEDDS. A design of experiments (DoE) approach was employed to develop SNEDDS incorporating medium-chain triglycerides (MCT), medium-chain mono- and diglycerides (MGDG), Kolliphor® RH40, and monoacyl phosphatidylcholine. SNEDDS with higher proportions of MGDG and Kolliphor® RH40 demonstrated a 9-fold reduction in droplet size (230 to 26 nm), a 1.5-fold decrease in lipolysis (0.23 to 0.34 mmol of FFA), and a 2-fold enhancement in exenatide protection against proteolysis (73 % to 38 %) compared to those with higher MCT content. Permeability studies in Caco-2 cells showed that SNEDDS with higher proportion of MGDG displayed a 40-fold increase in apparent permeability of FD4, when compared to SNEDDS with higher proportion of MCT. An oral gavage study in rats revealed a 1.8-fold higher absorption of Ex in SNEDDS with a higher proportion of MGDG and Kolliphor®RH40 compared to SNEDDS with higher MCT. These results establish a clear in vitro-in vivo correlation, demonstrating that the selected in vitro methods effectively differentiated formulations with high and low absorption of exenatide after oral dosing in rats.

MKP-2 Deficiency Leads to Lipolytic and Inflammatory Response to Fasting in Mice

MKP-2 Deficiency Leads to Lipolytic and Inflammatory Response to Fasting in Mice

Hepatic transcript profiling in beef cattle: Effects of rumen-protected niacin supplementation.

The objective of our study was to assess the effect of rumen-protected niacin supplementation on the transcriptome of liver tissue in growing Angus × Simmental steers and heifers through RNA-seq analysis. Consequently, we wanted to assess the known role of niacin in the physiological processes of vasodilation, detoxification, and immune function in beef hepatic tissue. Normal weaned calves (~8 months old) were provided either a control diet or a diet supplemented with rumen-protected niacin (6 g/hd/d) for a 30-day period, followed by a liver biopsy. We observed a significant list of changes at the transcriptome level due to rumen-protected niacin supplementation. Several metabolic pathways revealed potential positive effects to the animal's liver metabolism due to administration of rumen-protected niacin; for example, a decrease in lipolysis, apoptosis, inflammatory responses, atherosclerosis, oxidative stress, fibrosis, and vasodilation-related pathways. Therefore, results from our study showed that the liver transcriptional machinery switched several metabolic pathways to a condition that could potentially benefit the health status of animals supplemented with rumen-protected niacin. In conclusion, based on the results of our study, we can suggest the utilization of rumen-protected niacin supplementation as a nutritional strategy could improve the health status of growing beef cattle in different beef production stages, such as backgrounding operations or new arrivals to a feedlot.

Impact of Grape Seed Powder and Black Tea Brew on Lipid Digestion-An In Vitro Co-Digestion Study with Real Foods.

Effects of two foods with bioactive constituents (black tea brew, BTB and grape seed powder, GSP) on lipid digestibility was studied. Lipolysis inhibitory effect of these foods was examined using two test foods (cream and baked beef) with highly different fatty acid (FA) composition. Digestion simulations were performed either using both gastric and pancreatic lipase, or only with pancreatic lipase according to the Infogest protocol. Lipid digestibility was assessed based on the bioaccessible FAs. Results showed the triacylglycerols containing short- and medium-chain FAs (SCFA and MCFA) are non-preferred substrates for pancreatic lipase; however, this is not characteristic for GL. Our findings suggest that both GSP and BTB primarily affect the lipolysis of SCFAs and MCFAs, because the dispreference of pancreatic lipase towards these substrates was further enhanced as a result of co-digestion. Interestingly, GSP and BTB similarly resulted in significant decrease in lipolysis for cream (containing milk fat having a diverse FA profile), whereas they were ineffective in influencing the digestion of beef fat, having simpler FA profile. It highlights that the characteristics of the dietary fat source of a meal can be a key determinant on the observed extent of lipolysis when co-digested with foods with bioactive constituents.

A missense variant Arg611Cys in LIPE which encodes hormone sensitive lipase decreases lipolysis and increases risk of type 2 diabetes in American Indians.

Hormone sensitive lipase (HSL), encoded by the LIPE gene, is involved in lipolysis. Based on prior animal and human studies, LIPE was analysed as a candidate gene for the development of type 2 diabetes (T2D) in a community-based sample of American Indians. Whole-exome sequence data from 6782 participants with longitudinal clinical measures were used to identify variation in LIPE. Amongst the 16 missense variants identified, an Arg611Cys variant (rs34052647; Cys-allele frequency=0.087) significantly associated with T2D (OR [95% CI]=1.38 [1.17-1.64], p=0.0002, adjusted for age, sex, birth year, and the first five genetic principal components) and an earlier onset age of T2D (HR=1.22 [1.09-1.36], p=0.0005). This variant was further analysed for quantitative traits related to T2D. Amongst non-diabetic American Indians, those with the T2D risk Cys-allele had increased insulin levels during an oral glucose tolerance test (0.07 SD per Cys-allele, p=0.04) and a mixed meal test (0.08 log10 µU/ml per Cys-allele, p=0.003), and had increased lipid oxidation rates post-absorptively and during insulin infusion (0.07mg [kg estimated metabolic body size {EMBS}]-1 min-1 per Cys-allele for both, p=0.01 and 0.009, respectively), compared to individuals withthe non-risk Arg-allele. In vitro functional studies showed that cells expressing the Cys-allele had a 17.2% decrease in lipolysis under isoproterenol stimulation(p=0.03) and a 21.3% decrease in lipase enzyme activity measured by using p-nitrophenyl butyrate as a substrate (p=0.04) compared to the Arg-allele. The Arg611Cys variant causes a modest impairment in lipolysis, thereby affecting glucose homoeostasis and risk of T2D.

Dietary supplementation with rumen-protected capsicum during the transition period improves the metabolic status of dairy cows

In ruminants, it has been observed that capsicum oleoresin can alter insulin responses and that high-intensity artificial sweetener can increase glucose absorption from the small intestine. Because glucose metabolism and insulin responses are critical during early lactation, these supplements might have an effect on the metabolic status of dairy cows during the transition period. The objective of this experiment was to evaluate the effects of rumen-protected capsicum oleoresin fed alone or in combination with artificial sweetener during the transition period on lactational performance and susceptibility to subclinical ketosis in dairy cows. Fifteen primiparous and 30 multiparous Holstein cows (a total of 39 cows finished the study) were arranged in a randomized complete block design during d -21 to 60 relative to parturition. Cows within block were randomly assigned to one of the following treatments: no supplement (CON), supplementation with 100 mg of rumen-protected capsicum/cow per day (RPCap), or RPCap plus 2 g of high-intensity artificial sweetener/cow per day (RPCapS). For both the RPCap and RPCapS treatments, only rumen-protected capsicum was fed during the dry period. From d 8 to 11 of lactation, intake was limited to 70% of predicted dry matter intake to induce subclinical ketosis. Production variables were recorded daily, samples for milk composition were collected on wk 2, 4, 6, and 8, and blood samples were collected on wk -2, 1, 2, and 4 of the experiment for analysis of metabolic hormones and blood cell counts. Supplementation with rumen-protected capsicum increased serum insulin and decreased β-hydroxybutyrate concentrations precalving, indicating a decrease in lipolysis. During the lactation period, RPCap was associated with a trend for increased milk production and feed efficiency following the ketosis challenge. Supplementation with RPCapS appeared to negate the response to rumen-protected capsicum. All cows developed subclinical ketosis during the challenge, and this was not affected by treatment. We conclude that treatments did not decrease susceptibility to subclinical ketosis; however, dietary supplementation with rumen-protected capsicum was effective at improving energy status precalving and tended to increased milk production and feed efficiency. The mechanism underlying these responses is unclear.

Endocannabinoids Produced by White Adipose Tissue Modulate Lipolysis in Lean but Not in Obese Rodent and Human.

White adipose tissue (WAT) possesses the endocannabinoid system (ECS) machinery and produces the two major endocannabinoids (ECs), arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG). Accumulating evidence indicates that WAT cannabinoid 1 receptors (CB1R) are involved in the regulation of fat storage, tissue remodeling and secretory functions but their role in controlling lipid mobilization is unclear. In the present study, we used different strategies to acutely increase ECS activity in WAT and tested the consequences on glycerol production as a marker of lipolysis. Treating lean mice or rat WAT explants with JLZ195, which inhibits ECs degrading enzymes, induced an increase in 2-AG tissue contents that was associated with a CB1R-dependent decrease in lipolysis. Direct treatment of rat WAT explants with AEA also inhibited glycerol production while mechanistic studies revealed it could result from the stimulation of Akt-signaling pathway. Interestingly, AEA treatment decreased lipolysis both in visceral and subcutaneous WAT collected on lean subjects suggesting that ECS also reduces fat store mobilization in Human. In obese mice, WAT content and secretion rate of ECs were higher than in control while glycerol production was reduced suggesting that over-produced ECs may inhibit lipolysis activating local CB1R. Strikingly, our data also reveal that acute CB1R blockade with Rimonabant did not modify lipolysis in vitro in obese mice and human explants nor in vivo in obese mice. Taken together, these data provide physiological evidence that activation of ECS in WAT, by limiting fat mobilization, may participate in the progressive tissue remodeling that could finally lead to organ dysfunction. The present findings also indicate that acute CB1R blockade is inefficient in regulating lipolysis in obese WAT and raise the possibility of an alteration of CB1R signaling in conditions of obesity.

1H NMR Study of the In Vitro Digestion of Highly Oxidized Soybean Oil and the Effect of the Presence of Ovalbumin.

Oxidized lipids containing a wide variety of potentially toxic compounds can be ingested through diet. However, their transformations during digestion are little known, despite this knowledge being essential in understanding their impact on human health. Considering this, the in vitro digestion process of highly oxidized soybean oil, containing compounds bearing hydroperoxy, aldehyde, epoxy, keto and hydroxy groups, among others, is studied by 1H nuclear magnetic resonance. Lipolysis extent, oxidation occurrence and the fate of oxidation products both present in the undigested oil and formed during digestion are analyzed. Furthermore, the effect during digestion of two different ovalbumin proportions on all the aforementioned issues is also addressed. It is proved that polyunsaturated group bioaccessibility is affected by both a decrease in lipolysis and oxidation occurrence during digestion. While hydroperoxide level declines throughout this process, epoxy-compounds, keto-dienes, hydroxy-compounds, furan-derivatives and n-alkanals persist to a great extent or even increase. Conversely, α,β-unsaturated aldehydes, especially the very reactive and toxic oxygenated ones, diminish, although part of them remains in the digestates. While a low ovalbumin proportion hardly affects oil evolution during digestion, at a high level it diminishes oxidation and reduces the concentration of potentially bioaccessible toxic oxidation compounds.

P2Y 14 receptor regulates adipocyte lipid mobilization and whole‐body glucose homeostasis

The incidence and prevalence of obesity and type 2 diabetes (T2D) is rapidly increasing worldwide. Obesity is associated with chronically elevated plasma free fatty acid (FFA) levels, causing peripheral insulin resistance and T2D. Drugs that are able to regulate adipocyte lipolytic processes, improving insulin sensitivity and whole-body glucose homeostasis, have considerable therapeutic potential. Gi-coupled P2Y14 receptor (P2Y14R), activated by UDP-glucose is abundantly expressed in mouse and human adipocytes. P2Y14R activation in primary mouse adipocytes decreased cAMP levels and CL-316,243 (β3-adrenoceptor agonist) induced lipolysis. To investigate the physiological relevance of adipocyte P2Y14Rs in regulating lipid and glucose homeostasis in-vivo, we generated a mouse model lacking P2Y14R specifically in adipocytes. Lack of adipocyte P2Y14R increased lipolysis only in the fasting state, resulting in decreased body weight, improved glucose tolerance and insulin sensitivity. Accordingly, high fat diet increased, whereas fasting decreased P2Y14R expression in visceral white adipocytes. Mechanistic studies suggested that activation of P2Y14R reduced the activity of lipolytic enzymes including ATGL and HSL, thereby inhibiting lipolysis. Supporting these findings, administration of P2Y14R agonist in control mice decreased lipolysis. Coadministration of P2Y14R antagonist with the P2Y14R agonist rescued the decrease in lipolysis. In conclusion, we demonstrate that lack of adipocyte P2Y14R decreased diet-induced obesity by enhancing lipolysis in the fasting state, suggesting that P2Y14R antagonists may prove beneficial for the therapy of obesity and T2D.

Raw Milk Microbiota Modifications as Affected by Chlorine Usage for Cleaning Procedures: The Trentingrana PDO Case.

Milk microbiota represents a key point in raw milk cheese production and contributes to the development of typical flavor and texture for each type of cheese. The aim of the present study was to evaluate the influence of chlorine products usage for cleaning and sanitizing the milking equipment on (i) raw milk microbiota; (ii) the deriving whey-starter microbiota; and (iii) Trentingrana Protected Designation of Origin (PDO) cheese microbiota and volatilome. Milk samples from three farms affiliated to a Trentingrana PDO cheese factory were collected three times per week during a 6-weeks period in which a sodium hypochlorite detergent (period C) was used and during a subsequent 6-weeks period of non-chlorine detergent usage (period NC). Samples were subjected to microbiological [Standard Plate Count; coliforms; coagulase-positive staphylococci; and lactic acid bacteria (LAB)] and metagenomic analysis (amplification of V3-V4 regions of 16S rRNA gene performed on Illumina MiSeq platform). In addition, cheese volatilome was determined by SPME-GC-MS. In the transition from period C to period NC, higher SPC and LAB counts in milk were recorded. Milk metagenomic analysis showed a peculiar distinctive microbiota composition for the three farms during the whole experimental period. Moreover, differences were highlighted comparing C and NC periods in each farm. A difference in microbial population related to chlorine usage in bulk milk and vat samples was evidenced. Moreover, chlorine utilization at farm level was found to affect the whey-starter population: the usually predominant Lactobacillus helveticus was significantly reduced during NC period, whereas Lactobacillus delbrueckii had the exact opposite trend. Alpha- and beta-diversity revealed a separation between the two treatment periods with a higher presence of L. helveticus, L. delbrueckii, and Streptococcus thermophilus in cheese samples after NC detergent period. Cheese volatilome analysis showed a slight decrease in lipolysis during C period in the inner part of the cheese wheel. Although preliminary, these results suggest a profound influence on milk and cheese microbiota, as well as on raw milk cheese production and quality, due to the use of chlorine. However, further studies will be needed to better understand the complex relationship between chlorine and microbiota along all the cheese production steps.

2020-P: ß3-Adrenergic Receptors Regulate Lipolysis and Thermogenesis in Human Brown/Beige Adipocytes

Activation of rodent brown adipose tissue (BAT) via pharmacological stimulation of β3-adrenergic receptors (β3-AR) leads to metabolic benefit, however in humans, the physiological relevance of BAT and β3-AR remain controversial. To investigate the role of the β3-AR in human brown adipocytes, first, we established a human primary supraclavicular adipocyte in vitro model that upon differentiation preserved the physiological properties brown adipose tissue with increased β-ARs, adipogenic, thermogenic and brown/beige markers. Next, we selective silenced β3-AR expression in differentiated primary brown/beige adipocytes using a lipofectamine-based non-viral transfection. 48h of transfection of siRNA targeting ADRB3 (siRNA-ADRB3) resulted in a 90% reduction in ADRB3 mRNA levels, relative to control siRNA-transfected cells (siRNA-Ctrl). siRNA-ADRB3 also reduced genes of fatty acid metabolism, thermogenesis (UCP1, 90% decrease), and mitochondrial mass. Functionally, lower cAMP levels, lipolysis, oxygen consumption rates and higher glycolysis were caused by silencing β3-AR receptor. Immortalized brown adipocyte (hBA’s), from a separate subject, displayed a similar decrease in lipolysis and cellular respiration. Mirabegron, the selective human β3-AR agonist, stimulated BAT lipolysis and thermogenesis, that were lost after knockdown ADRB3. Similarly, selective subtype human β-AR agonists dobutamine (β1-AR agonist) and terbutaline (β2-AR agonist) treatment also increased lipolysis and thermogenesis, that were also attenuated when β3-AR was silenced. Thus, the β3-AR maintains multiple components of the human brown/beige adipocyte lipolytic and thermogenic cellular machinery. These findings indicate that ADRB3 and β3-AR agonists could be used to achieve metabolic benefit in humans. Disclosure C. Cero: None. H.J. Lea: None. K.Y. Zhu: None. A.M. Cypess: None.

Influence of Aging and Menstrual Status on Subcutaneous Fat Cell Lipolysis.

Aging is accompanied by inhibited fat cell mobilization of fatty acids through lipolysis, which may contribute to decreased energy expenditure in elderly subjects. However, the influence of menstrual status is unknown. To investigate the role of menstrual status on changes in lipolysis induced by aging. A longitudinal investigation with a mean 13-year interval. Ambulatory study at a clinical academic unit. Eighty-two continuously recruited women between 24 and 62 years of age and with body mass index 21 to 48 kg/m2 at first examination. Twenty-nine women continued to have normal menstruation, 42 developed irregular menstruation/menopause, and 11 had a perimenstrual/menopausal phenotype already at the first examination. Lipolysis measured as glycerol release from isolated subcutaneous fat cells incubated in vitro. On average, body weight/body fat mass levels did not change over time. In all 3 groups, aging was associated with a similar decrease in spontaneous (basal) and catecholamine-stimulated lipolysis. The latter was due to decreased signal transduction through stimulatory beta adrenoceptors and increased alpha-2-adrenoceptor-mediated antilipolytic effects. Gene microarray data from adipose tissue at baseline and follow-up (n = 53) showed that a limited set of lipolysis-linked genes, including phosphodiesterase-3B, were altered over time, but this was independent of menstrual status. Fat cell size also decreased during aging, but this could not explain the decrease in lipolysis. In women, the rate of fat cell lipolysis decreases during aging due to multiple alterations in spontaneous (basal) and catecholamine-induced lipolysis. This is independent of changes in menstrual status or fat cell size.

Histomorphological changes in the pancreas and kidney and histopathological changes in the liver in male Wistar rats on antiretroviral therapy and melatonin treatment

Combination antiretroviral therapy (cART) has shown to cause inflammation, cellular injury and oxidative stress, whereas melatonin has been successful in reducing these effects. The aim of the study was to determine potential morphometric changes caused by cART in combination with melatonin supplementation in human immunodeficiency virus (HIV)-free rats.Tissue samples (N = 40) of the pancreas, liver and kidney from a control (C/ART-/M-), cART group (C/ART + ), melatonin (C/M + ) and experimental group (ART+/M + ) were collected and stained with haematoxylin and eosin (H&E) and evaluated for histopathology. The pancreata were labelled with anti-insulin and anti-glucagon to determine α- and β-cell regions. Kidneys were stained with periodic acid Schiff (PAS) to measure the area, perimeter, diameter and radius of renal corpuscles, glomeruli and proximal convoluted tubules (PCTs). Blood tests were conducted to determine hepatotoxicity.No significant changes in histopathology were seen. Melatonin stimulated pancreatic islet abundance, as the number of islets per mm2 was significantly higher in the C/M+ than in the C/ART-/M- and ART+/M+. Parameters of the renal corpuscle, glomeruli, renal space and PCTs were significantly lower in the C/ART+ compared to the other groups, thus cART may have caused tubular dysfunction or cellular damage. A significant increase in serum haemoglobin was observed in the C/ART+ compared to the C/ART-, which showed cART increases serum haemoglobin in the absence of immune deficiency. Serum lipids were significantly decreased in the C/M+ compared to the C/ART-, possibly due to the effect of melatonin on the decrease of lipolysis, decreasing effect on cholesterol absorption and stimulation of lipoprotein lipase (LPL) activity.In conclusion, we have demonstrated that melatonin stimulated α-cell production, increased the number of pancreatic islets and caused a decrease in total lipids, whereas cART increased serum haemoglobin and decreased various parameters of the nephron in an HIV-free rat model, suggestive of tubular dysfunction.

Palmitate induces fat accumulation by activating C/EBPβ-mediated G0S2 expression in HepG2 cells.

AIMTo determine the role of G0/G1 switch gene 2 (G0S2) and its transcriptional regulation in palmitate-induced hepatic lipid accumulation.METHODSHepG2 cells were treated with palmitate, or palmitate in combination with CCAAT/enhancer binding protein (C/EBP)β siRNA or G0S2 siRNA. The mRNA expression of C/EBPβ, peroxisome proliferator-activated receptor (PPAR)γ and PPARγ target genes (G0S2, GPR81, GPR109A and Adipoq) was examined by qPCR. The protein expression of C/EBPβ, PPARγ, and G0S2 was determined by Western blotting. Lipid accumulation was detected with Oil Red O staining and quantified by absorbance value of the extracted Oil Red O dye. Lipolysis was evaluated by measuring the amount of glycerol released into the medium.RESULTSPalmitate caused a dose-dependent increase in lipid accumulation and a dose-dependent decrease in lipolysis in HepG2 cells. In addition, palmitate increased the mRNA expression of C/EBPβ, PPARγ, and PPARγ target genes (G0S2, GPR81, GPR109A, and Adipoq) and the protein expression of C/EBPβ, PPARγ, and G0S2 in a dose-dependent manner. Knockdown of C/EBPβ decreased palmitate-induced PPARγ and its target genes (G0S2, GPR81, GPR109A, and Adipoq) mRNA expression and palmitate-induced PPARγ and G0S2 protein expression in HepG2 cells. Knockdown of C/EBPβ also attenuated lipid accumulation and augmented lipolysis in palmitate-treated HepG2 cells. G0S2 knockdown attenuated lipid accumulation and augmented lipolysis, while G0S2 knockdown had no effects on the mRNA expression of C/EBPβ, PPARγ, and PPARγ target genes (GPR81, GPR109A and Adipoq) in palmitate-treated HepG2 cells.CONCLUSIONPalmitate can induce lipid accumulation in HepG2 cells by activating C/EBPβ-mediated G0S2 expression.

Papers of note in Nature 550 (7674)

This week’s articles highlight retrograde semaphorin signaling at synapses; a driver of age-related decreases in lipolysis; and a mechanism by which melanoma cells become resistant to combined therapies.

Sympathetic nervous system activity and anti-lipolytic response to iv-glucose load in subcutaneous adipose tissue of obese and obese type 2 diabetic subjects.

The study aim was to investigate the effect of endogenous insulin release on lipolysis in subcutaneous adipose tissue after adrenergic stimulation in obese subjects diagnosed with type 2 diabetes (T2D). In 14 obese female T2D subjects, or 14 obese non-T2D controls, glycerol concentration was measured in response to the α1,2,ß-agonist norepinephrine, the α1-agonist norfenefrine and the ß2-agonist terbutaline (each 10−4 M), using the microdialysis technique. After 60 minutes of stimulation, an intravenous glucose load (0.5 g/kg lean body mass) was given. Local blood flow was monitored by means of the ethanol technique. Norepinephrine and norfenefrine induced a four and three fold rise in glycerol dialysate concentration (p<0.001, each), with a similar pattern in adipose tissue. Following agonist stimulation and glucose infusion, endogenous insulin release inhibited lipolysis in the presence of norepinephrine, which was more rapid and pronounced in healthy obese controls than in T2D subjects (p = 0.024 obese vs T2D subjects). Insulin-induced inhibition of lipolysis in the presence of norfenefrine was similar in all study participants. In the presence of terbutaline the lipolysis rate increased two fold until the effect of endogenous insulin (p<0.001). A similar insulin-induced decrease in lipolysis was observed for each of the norfenefrine groups and the terbutaline groups, respectively. Adipose tissue blood flow remained unchanged after the iv-glucose load. Both norepinephrine and norfenefrine diminished blood flow slightly, but insulin reversed this response (p<0.001 over the entire time). Terbutaline alone and terbutaline plus increased endogenous insulin augmented local blood flow (p<0.001 over the entire time). In conclusion, a difference in insulin-induced inhibition of lipolysis was observed in obese T2D subjects compared to obese healthy controls following modulation of sympathetic nervous system activity and is assumed to be due to ß1-adrenoceptor mediated stimulation by norepinephrine.

Mechanism for leptin's acute insulin-independent effect to reverse diabetic ketoacidosis.

The mechanism by which leptin reverses diabetic ketoacidosis (DKA) is unknown. We examined the acute insulin-independent effects of leptin replacement therapy in a streptozotocin-induced rat model of DKA. Leptin infusion reduced rates of lipolysis, hepatic glucose production (HGP), and hepatic ketogenesis by 50% within 6 hours and were independent of any changes in plasma glucagon concentrations; these effects were abrogated by coinfusion of corticosterone. Treating leptin- and corticosterone-infused rats with an adipose triglyceride lipase inhibitor blocked corticosterone-induced increases in plasma glucose concentrations and rates of HGP and ketogenesis. Similarly, adrenalectomized type 1 diabetic (T1D) rats exhibited decreased rates of lipolysis, HGP, and ketogenesis; these effects were reversed by corticosterone infusion. Leptin-induced decreases in lipolysis, HGP, and ketogenesis in DKA were also nullified by relatively small increases (15 to 70 pM) in plasma insulin concentrations. In contrast, the chronic glucose-lowering effect of leptin in a STZ-induced mouse model of poorly controlled T1D was associated with decreased food intake, reduced plasma glucagon and corticosterone concentrations, and decreased ectopic lipid (triacylglycerol/diacylglycerol) content in liver and muscle. Collectively, these studies demonstrate marked differences in the acute insulin-independent effects by which leptin reverses fasting hyperglycemia and ketoacidosis in a rodent model of DKA versus the chronic pleotropic effects by which leptin reverses hyperglycemia in a non-DKA rodent model of T1D.

Inositol hexakisphosphate kinase-1 interacts with perilipin1 to modulate lipolysis

Lipolysis leads to the breakdown of stored triglycerides (TAG) to release free fatty acids (FFA) and glycerol which is utilized by energy expenditure pathways to generate energy. Therefore, a decrease in lipolysis augments fat accumulation in adipocytes which promotes weight gain. Conversely, if lipolysis is not complemented by energy expenditure, it leads to FFA induced insulin resistance and type-2 diabetes. Thus, lipolysis is under stringent physiological regulation, although the precise mechanism of the regulation is not known. Deletion of inositol hexakisphosphate kinase-1 (IP6K1), the major inositol pyrophosphate biosynthetic enzyme, protects mice from high fat diet (HFD) induced obesity and insulin resistance. IP6K1-KO mice are lean due to enhanced energy expenditure. Therefore, IP6K1 is a target in obesity and type-2 diabetes. However, the mechanism/s by which IP6K1 regulates adipose tissue lipid metabolism is yet to be understood. Here, we demonstrate that IP6K1-KO mice display enhanced basal lipolysis. IP6K1 modulates lipolysis via its interaction with the lipolytic regulator protein perilipin1 (PLIN1). Furthermore, phosphorylation of IP6K1 at a PKC/PKA motif modulates its interaction with PLIN1 and lipolysis. Thus, IP6K1 is a novel regulator of PLIN1 mediated lipolysis.

Response of plasma glucose, insulin, and nonesterified fatty acids to intravenous glucose tolerance tests in dairy cows during a 670-day lactation

This experiment investigated the metabolic response of dairy cows undergoing an extended lactation to a frequently sampled intravenous glucose tolerance test. The experiment used 12 multiparous Holstein cows that calved in late winter in a seasonally calving pasture-based system and were managed for a 670-d lactation by delaying rebreeding. In each of four 5-wk experimental periods commencing at approximately 73, 217, 422, and 520 (±9.1) days in milk (DIM), cows were offered a diet of perennial ryegrass (73 and 422 DIM) or pasture hay and silage (217 and 520 DIM) supplemented with 1kg of DM grain (control; CON) or 6kg of DM grain (GRN) as a ration. Daily energy intake was approximately 160 and 215 MJ of metabolizable energy/cow for the CON and GRN treatments, respectively. At all other times, cows were managed as a single herd and grazed pasture supplemented with grain to an estimated minimum daily total intake of 180 MJ of metabolizable energy/cow. Cows were fitted with an indwelling jugular catheter during the final week of each experimental period. The standard intravenous glucose tolerance test using 0.3g of glucose per kilogram of body weight was performed on each cow at approximately 100, 250, 460, and 560 DIM. Plasma concentrations of glucose, insulin, and nonesterified fatty acids (NEFA) responses were measured. Milk yield, milk solids yield, body weight, and basal plasma glucose were greater in the GRN compared with the CON treatment. The area under the plasma response curve relative to baseline (AUC) for glucose, insulin, and NEFA and their apparent fractional clearance rates indicated varied whole body responsiveness to insulin in terms of glucose metabolism throughout the 670-d lactation. The glucose AUC 0 to 20 min postinfusion was increased at 560 DIM, indicating reduced utilization of glucose by the mammary gland at this stage of lactation. The NEFA clearance rate, 6 to 30 min postinfusion, was greater at 460 and 560 DIM. These data indicated an increase in lipogenic activity or a decrease in lipolysis as lactation progressed, suggestive of an overall increase in responsiveness to insulin in terms of whole body lipid metabolism as lactation progressed. These observations are consistent with decreased priority of lactation beyond 300 DIM. Cows in the GRN treatment had decreased whole body responsiveness to hyperglycemia compared with CON cows in terms of glucose clearance and AUC for the glucose response. Variation in the response curves of plasma glucose, NEFA, and insulin was predominantly a result of stage of lactation and not diet. This may be due to changes in mammary gland uptake of glucose that is independent of insulin and the responsiveness of peripheral tissues to the actions of insulin at different stages of the lactation that are independent of diet.

Is bisphenol S a safe substitute for bisphenol A in terms of metabolic function? An in vitro study

As bisphenol A (BPA) has been shown to induce adverse effects on human health, especially through the activation of endocrine pathways, it is about to be withdrawn from the European market and replaced by analogues such as bisphenol S (BPS). However, toxicological data on BPS is scarce, and so it is necessary to evaluate the possible effects of this compound on human health. We compared the effect of BPA and BPS on obesity and hepatic steatosis processes using low doses in the same range as those found in the environment. Two in vitro models were used, the adipose cell line 3T3-L1 and HepG2 cells, representative of hepatic functions. We analyzed different parameters such as lipid and glucose uptakes, lipolysis, leptin production and the modulation of genes involved in lipid metabolism and energy balance. BPA and BPS induced an increase in the lipid content in the 3T3-L1 cell line and more moderately in the hepatic cells. We also observed a decrease in lipolysis after bisphenol treatment of adipocytes, but only BPS was involved in the increase in glucose uptake and leptin production. These latter effects could be linked to the modulation of SREBP-1c, PPARγ, aP2 and ERRα and γ genes after exposure to BPA, whereas BPS seems to target the PGC1α and the ERRγ genes. The findings suggest that both BPA and BPS could be involved in obesity and steatosis processes, but through two different metabolic pathways.