Hepatic lipid-associated macrophages mediate the beneficial effects of bariatric surgery against MASH.

For patients with obesity and metabolic syndrome, bariatric procedures such as vertical sleeve gastrectomy (VSG) have a clear benefit in ameliorating metabolic dysfunction-associated steatohepatitis (MASH). While the effects of bariatric surgeries have been mainly attributed to nutrient restriction and malabsorption, whether immuno-modulatory mechanisms are involved remains unclear. Here we report that VSG ameliorates MASH progression in a weight loss-independent manner. Single-cell RNA sequencing revealed that hepatic lipid-associated macrophages (LAMs) expressing the triggering receptor expressed on myeloid cells 2 (TREM2) increase their lysosomal activity and repress inflammation in response to VSG. Remarkably, TREM2 deficiency in mice ablates the reparative effects of VSG, suggesting that TREM2 is required for MASH resolution. Mechanistically, TREM2 prevents the inflammatory activation of macrophages and is required for their efferocytotic function. Overall, our findings indicate that bariatric surgery improves MASH through a reparative process driven by hepatic LAMs, providing insights into the mechanisms of disease reversal that may result in new therapies and improved surgical interventions.

ACOT1 deficiency attenuates high-fat diet-induced fat mass gain by increasing energy expenditure.

Acyl-CoA thioesterase 1 (ACOT1) catalyzes the hydrolysis of long-chain acyl-CoAs to free fatty acids and CoA and is typically upregulated in obesity. Whether targeting ACOT1 in the setting of high-fat diet-induced (HFD-induced) obesity would be metabolically beneficial is not known. Here we report that male and female ACOT1KO mice are partially protected from HFD-induced obesity, an effect associated with increased energy expenditure without alterations in physical activity or food intake. In males, ACOT1 deficiency increased mitochondrial uncoupling protein-2 (UCP2) protein abundance while reducing 4-hydroxynonenal, a marker of oxidative stress, in white adipose tissue and liver of HFD-fed mice. Moreover, concurrent knockdown (KD) of UCP2 with ACOT1 in hepatocytes prevented increases in oxygen consumption observed with ACOT1 KD during high lipid loading, suggesting that UCP2-induced uncoupling may increase energy expenditure to attenuate weight gain. Together, these data indicate that targeting ACOT1 may be effective for obesity prevention during caloric excess by increasing energy expenditure.

Organelle interactions compartmentalize hepatic fatty acid trafficking and metabolism.

Organelle interactions play a significant role in compartmentalizing metabolism and signaling. Lipid droplets (LDs) interact with numerous organelles, including mitochondria, which is largely assumed to facilitate lipid transfer and catabolism. However, quantitative proteomics of hepatic peridroplet mitochondria (PDM) and cytosolic mitochondria (CM) reveals that CM are enriched in proteins comprising various oxidative metabolism pathways, whereas PDM are enriched in proteins involved in lipid anabolism. Isotope tracing and super-resolution imaging confirms that fatty acids (FAs) are selectively trafficked to and oxidized in CM during fasting. In contrast, PDM facilitate FA esterification and LD expansion in nutrient-replete medium. Additionally, mitochondrion-associated membranes (MAM) around PDM and CM differ in their proteomes and ability to support distinct lipid metabolic pathways. We conclude that CM and CM-MAM support lipid catabolic pathways, whereas PDM and PDM-MAM allow hepatocytes to efficiently store excess lipids in LDs to prevent lipotoxicity.

Time-restricted eating did not alter insulin sensitivity or ß-cell function in adults with obesity: A randomized pilot study.

OBJECTIVE: Decreased insulin sensitivity and impairment of ß-cell function predate and predict development of type 2 diabetes mellitus. Time-restricted eating (TRE) might have a benefit for these parameters. The objective of this pilot study was to investigate this possibility. METHODS: Secondary analysis of a randomized controlled trial comparing 12 weeks of TRE (8-hour eating window) to unrestricted eating (non-TRE) was performed. Participants were adults with overweight or obesity and without diabetes. Two-hour oral glucose tolerance testing was performed at baseline and end-intervention. Glucose tolerance test-derived measures of insulin sensitivity, insulin secretion, and ß-cell function were compared between groups. RESULTS: Participants (17 women/3 men with mean [SD] age 45.5 [12.1] years and BMI 34.1 [7.5] kg/m2 ) with a prolonged eating window (15.4 [0.9] hours) were randomized to TRE (n = 11) or non-TRE (n = 9). The quantitative insulin sensitivity check index (QUICKI), Stumvoll index, Avignon index, insulinogenic index, insulin area under the curve/glucose area under the curve, and oral disposition index did not differ between the TRE and non-TRE groups at end-intervention. CONCLUSIONS: In adults with overweight or obesity and without diabetes, TRE did not significantly alter insulin sensitivity, insulin secretion, or ß-cell function over a 12-week intervention. Whether TRE is beneficial in adults with prediabetes or type 2 diabetes mellitus warrants further investigation.

Kinetic-model-based pathway optimization with application to reverse glycolysis in mammalian cells.

Over the last two decades, model-based metabolic pathway optimization tools have been developed for the design of microorganisms to produce desired metabolites. However, few have considered more complex cellular systems such as mammalian cells, which requires the use of nonlinear kinetic models to capture the effects of concentration changes and cross-regulatory interactions. In this study, we develop a new two-stage pathway optimization framework based on kinetic models that incorporate detailed kinetics and regulation information. In Stage 1, a set of optimization problems are solved to identify and rank the enzymes that contribute the most to achieving the metabolic objective. Stage 2 then determines the optimal enzyme interventions for specified desired numbers of enzyme adjustments. It also incorporates multi-scenario optimization, which allows the simultaneous consideration of multiple physiological conditions. We apply the proposed framework to find enzyme adjustments that enable a reverse glucose flow in cultured mammalian cells, thereby eliminating the need for glucose feed in the late culture stage and enhancing process robustness. The computational results demonstrate the efficacy of the proposed approach; it not only captures the important regulations and key enzymes for reverse glycolysis but also identifies differences and commonalities in the metabolic requirements for different carbon sources.

Predicting energy intake with an accelerometer-based intake-balance method.

Nutritional interventions often rely on subjective assessments of energy intake (EI), but these are susceptible to measurement error. To introduce an accelerometer-based intake-balance method for assessing EI using data from a time-restricted eating (TRE) trial. Nineteen participants with overweight/obesity (25-63 years old; 16 females) completed a 12-week intervention (NCT03129581) in a control group (unrestricted feeding; n 8) or TRE group (n 11). At the start and end of the intervention, body composition was assessed by dual-energy X-ray absorptiometry (DXA) and daily energy expenditure (EE) was assessed for 2 weeks via wrist-worn accelerometer. EI was back-calculated as the sum of net energy storage (from DXA) and EE (from accelerometer). Accelerometer-derived EI estimates were compared against estimates from the body weight planner of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Mean EI for the control group declined by 138 and 435 kJ/day for the accelerometer and NIDDK methods, respectively (both P ≥ 0·38), v. 1255 and 1469 kJ/day, respectively, for the TRE group (both P < 0·01). At follow-up, the accelerometer and NIDDK methods showed excellent group-level agreement (mean bias of -297 kJ/day across arms; standard error of estimate 1054 kJ/day) but high variability at the individual level (limits of agreement from -2414 to +1824 kJ/day). The accelerometer-based intake-balance method showed plausible sensitivity to change, and EI estimates were biologically and behaviourally plausible. The method may be a viable alternative to self-report EI measures. Future studies should assess criterion validity using doubly labelled water.

The impact of a self-selected time restricted eating intervention on eating patterns, sleep, and late-night eating in individuals with obesity.

Background: Time restricted eating (TRE), limiting eating to a specific daily window, is a novel dietary intervention, but the mechanisms by which TRE results in weight loss remain unclear. The goal of the current study was to examine changes in eating patterns, sleep, and late-night eating, and associations with health outcomes in a secondary analysis of a 12-week self-selected TRE intervention. Methods: Twenty participants 18-65 years with BMI ≥25 kg/m2 completed the 12-week trial. Participants randomized to TRE (n = 11) were instructed to eat during a self-selected 8-h window, while the non-TRE group (n = 9) followed their typical eating habits. All participants logged oral intake using the myCircadian Clock mobile application throughout the entire intervention. Anthropometrics, HbA1c, an oral glucose tolerance test, and 2 weeks of actigraphy monitoring were completed at pre-intervention and end-intervention. Independent samples t-tests compared differences between groups. Data are presented as mean ± standard deviation. Results: At preintervention, late night eating was significantly associated with higher fasting glucose (r = 0.59, p = 0.006) and higher HbA1c (r = 0.46, p = 0.016). The TRE group significantly delayed the timing of the first eating occasion by 2.72 ± 1.48 h relative to wake time (p < 0.001) and advanced the timing of the last eating occasion by 1.25 ± 0.8 h relative to bedtime (p < 0.001). The non-TRE group, on average, maintained their eating pattern. Sleep measures did not change from pre- to end-intervention, however greater restriction of the eating window was associated with longer sleep duration at end-intervention (ß = -0.46 [95% CI -9.2, -0.4], p = 0.03). The TRE group significantly reduced the prevalence of late night eating (eating within 2 h of bedtime) by 14 ± 6% (p = 0.028) with 63% of participants completely eliminating late night eating at end-intervention. Conclusion: A self-selected TRE intervention significantly shifted meal timing, reduced late-night eating while prolonging sleep duration. Trial registry: ClinicalTrials.gov, identifier: 03129581.

Systemic lipolysis promotes physiological fitness in Drosophila melanogaster.

Since interventions such as caloric restriction or fasting robustly promote lipid catabolism and improve aging-related phenotypical markers, we investigated the direct effect of increased lipid catabolism via overexpression of bmm (brummer, FBgn0036449), the major triglyceride hydrolase in Drosophila, on lifespan and physiological fitness. Comprehensive characterization was carried out using RNA-seq, lipidomics and metabolomics analysis. Global overexpression of bmm strongly promoted numerous markers of physiological fitness, including increased female fecundity, fertility maintenance, preserved locomotion activity, increased mitochondrial biogenesis and oxidative metabolism. Increased bmm robustly upregulated the heat shock protein 70 (Hsp70) family of proteins, which equipped the flies with higher resistance to heat, cold, and ER stress via improved proteostasis. Despite improved physiological fitness, bmm overexpression did not extend lifespan. Taken together, these data show that bmm overexpression has broad beneficial effects on physiological fitness, but these effects did not impact lifespan.

Isolated and combined impact of dietary olive oil and exercise on markers of health and energy metabolism in female mice.

An olive oil (OO) rich diet or high-intensity interval training (HIIT) independently improve markers of health and energy metabolism, but it is unknown if combining OO and HIIT synergize to improve these markers. This study characterized the isolated and combined impact of OO and HIIT on markers of health and energy metabolism in various tissues in C57BL/6J female mice. Nine-week-old mice were divided into four groups for a 12-week diet and/or exercise intervention including: (1) Control Diet without HIIT (CD), (2) Control Diet with HIIT (CD+HIIT), (3) OO diet (10% kcal from olive oil) without HIIT, and (4) OO diet with HIIT (OO+HIIT). Neither dietary OO or HIIT altered body weight, glucose tolerance, or serum lipids. HIIT, regardless of diet, increased aerobic capacity and HDL cholesterol levels. In liver and heart tissue, OO resulted in similar adaptations as HIIT including increased mitochondrial content and fatty acid oxidation but combining OO with HIIT did not augment these effects. In skeletal muscle, HIIT increased mitochondrial content in type II fibers similarly between diets. An RNA sequencing analysis on type I fibers revealed OO reduced muscle regeneration and lipid metabolism gene abundance, whereas HIIT increased the abundance of these genes, independent of diet. HIIT training, independent of diet, induced subcutaneous white adipose tissue (sWAT) hypertrophy, whereas OO induced gonadal white adipose tissue (gWAT) hypertrophy, an effect that was augmented with HIIT. These data highlight the pleiotropic effects of OO and HIIT, although their combination does not synergize to further improve most markers of health and energy metabolism.

Perilipins at a glance.

Lipid droplets (LDs) are ubiquitous organelles that store and supply lipids for energy metabolism, membrane synthesis and production of lipid-derived signaling molecules. While compositional differences in the phospholipid monolayer or neutral lipid core of LDs impact their metabolism and function, the proteome of LDs has emerged as a major influencer in all aspects of LD biology. The perilipins (PLINs) are the most studied and abundant proteins residing on the LD surface. This Cell Science at a Glance and the accompanying poster summarize our current knowledge of the common and unique features of the mammalian PLIN family of proteins, the mechanisms through which they affect cell metabolism and signaling, and their links to disease.

Regulation and role of glycophagy in skeletal muscle energy metabolism.

Glycophagy is the autophagic degradation of glycogen via the lysosomal enzyme GAA/alpha-acid glucosidase. Glycophagy is considered a housekeeping process to degrade poorly branched glycogen particles, but the regulation and role of glycophagy in skeletal muscle metabolism remains enigmatic. Herein, prior muscle contraction promoted glycogen supercompensation 24 and 48 h post contraction, an effect associated with reduced glycophagy. Moreover, NOTCH or cAMP signaling promoted glycophagy, whereas acute glycophagy deficiency rewired cell metabolism by reducing glycolysis and enhancing AMPK and PPAR signaling and fatty acid and glutamine metabolism. These metabolic adaptations were associated with reduced inflammation and triglyceride content but enhanced phosphoinositide 3-kinase (PI3K)-AKT/protein kinase B signaling and insulin action, the latter of which was abolished by exogenous oxidative stress. Collectively, these data suggest glycophagy is dynamically regulated, while the function of glycophagy can be extended beyond a housekeeping process to having an additional role in regulating energy metabolism and insulin action.Abbreviations: AMPK, AMP-activated protein kinase; ASM, acid soluble metabolites; cAMP, cyclic adenosine monophosphate; EPS, electrical pulse stimulation; FCCP, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; GAA, glucosidase, alpha, acid; mTOR, mechanistic target of rapamycin kinase; NAD, nicotinamide adenine dinucleotide; PARP, poly (ADP-ribose) polymerase family; PI3K, phosphoinositide 3-kinase; PPAR, peroxisome proliferator activated receptor ; PYGM, muscle glycogen phosphorylase; STBD1, starch binding domain 1; TFEB, transcription factor EB.

Hepatic lysosomal acid lipase overexpression worsens hepatic inflammation in mice fed a Western diet.

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipid droplets in hepatocytes. NAFLD development and progression is associated with an increase in hepatic cholesterol levels and decreased autophagy and lipophagy flux. Previous studies have shown that the expression of lysosomal acid lipase (LAL), encoded by the gene LIPA, which can hydrolyze both triglyceride and cholesteryl esters, is inversely correlated with the severity of NAFLD. In addition, ablation of LAL activity results in profound NAFLD. Based on this, we predicted that overexpressing LIPA in the livers of mice fed a Western diet would prevent the development of NAFLD. As expected, mice fed the Western diet exhibited numerous markers of NAFLD, including hepatomegaly, lipid accumulation, and inflammation. Unexpectedly, LAL overexpression did not attenuate steatosis and had only minor effects on neutral lipid composition. However, LAL overexpression exacerbated inflammatory gene expression and infiltration of immune cells in mice fed the Western diet. LAL overexpression also resulted in abnormal phagosome accumulation and lysosomal lipid accumulation depending upon the dietary treatment. Overall, we found that hepatic overexpression of LAL drove immune cell infiltration and inflammation and did not attenuate the development of NAFLD, suggesting that targeting LAL expression may not be a viable route to treat NAFLD in humans.

Phosphatase PHLPP2 regulates the cellular response to metabolic stress through AMPK.

PHLPP2 is a member of the PHLPP family of phosphatases, known to suppress cell growth by inhibiting proliferation or promoting apoptosis. Oncogenic kinases Akt, S6K, and PKC, and pro-apoptotic kinase Mst1, have been recognized as functional targets of the PHLPP family. However, we observed that, in T-leukemia cells subjected to metabolic stress from glucose limitation, PHLPP2 specifically targets the energy-sensing AMP-activated protein kinase, pAMPK, rather than Akt or S6K. PHLPP2 dephosphorylates pAMPK in several other human cancer cells as well. PHLPP2 and pAMPK interact with each other, and the pleckstrin homology (PH) domain on PHLPP2 is required for their interaction, for dephosphorylating and inactivating AMPK, and for the apoptotic response of the leukemia cells to glucose limitation. Silencing PHLPP2 protein expression prolongs the survival of leukemia cells subjected to severe glucose limitation by promoting a switch to AMPK-mediated fatty acid oxidation for energy generation. Thus, this study reveals a novel role for PHLPP2 in suppressing a survival response mediated through AMPK signaling. Given the multiple ways in which PHLPP phosphatases act to oppose survival signaling in cancers and the pivotal role played by AMPK in redox homeostasis via glucose and fatty acid metabolism, the revelation that AMPK is a target of PHLPP2 could lead to better therapeutics directed both at cancer and at metabolic diseases.

Chromatin accessibility profiling identifies evolutionary conserved loci in activated human satellite cells.

Satellite cells represent the main myogenic population accounting for skeletal muscle homeostasis and regeneration. While our knowledge of the signaling pathways controlling satellite cell regenerative capability is increasing, the underlying epigenetic mechanisms are still not clear, especially in the case of human satellite cells. Here, by performing chromatin accessibility profiling (ATAC-seq) in samples isolated from human and murine muscles, we investigated the changes in the epigenetic landscape occurring during the transition from activated satellite cells to myoblasts. Our analysis identifies a compendium of putative regulatory elements defining human activated satellite cells and myoblasts, respectively. A subset of these differentially accessible loci is shared by both murine and human satellite cells, includes elements associated with known self-renewal regulators, and is enriched for motifs bound by transcription factors participating in satellite cell regulation. Integration of transcriptional and epigenetic data reveals that known regulators of metabolic gene expression, such as PPARGC1A, represent potential PAX7 targets. Through characterization of genomic networks and the underlying effectors, our data represent an important starting point for decoding and manipulating the molecular mechanisms underlying human satellite cell muscle regenerative potential.

Time-Restricted Eating Improves Quality of Life Measures in Overweight Humans.

Time-restricted eating (TRE) reduces weight in humans, but its effects on quality of life have not been well characterized. By performing a secondary analysis of a randomized clinical trial, we examined the effects of TRE (12-week intervention, 8 h eating window) vs. non-TRE (unrestricted eating) on quality of life (QoL) measures. Twenty subjects with overweight and prolonged eating window (mean (SD): 15.4 h (0.9)) were randomized to either 12 weeks of TRE (8 h eating window: (n = 11)) or non-TRE (n = 9). QoL data were collected with the 36-item Short Form Survey (SF-36) pre- and post-intervention. Given a two-way ANOVA model and post-hoc t-test analysis, the TRE group improved limitations due to emotional health post-intervention: +97.0 (10.0)) vs. baseline: +66.7 (42.2) (p = 0.02) and perceived change in health over the last year end intervention: +68.2 (16.2) vs. baseline: +52.3 (23.6) (p = 0.001) relative to baseline. The TRE group improved limitations due to emotional health TRE: +97.0 (10.0) vs. non-TRE: +55.6 (44.1) (p = 0.05) and perceived change in health (TRE: +68.2 (16.2) vs. non-TRE: +44.4 (31.6) (p = 0.04) relative to the non-TRE group at post-intervention (p < 0.025). In conclusion, 12 weeks of TRE does not adversely affect QoL and may be associated with modest improvements in QoL relative to baseline and unrestricted eating; these findings support future studies examining TRE compliance and durability.

Time-Restricted Eating for 12 Weeks Does Not Adversely Alter Bone Turnover in Overweight Adults.

Weight loss is a major focus of research and public health efforts. Time-restricted eating (TRE) is shown to be effective for weight loss, but the impact on bone is unclear. Short-term TRE studies show no effect on bone mineral density (BMD), but no study has measured bone turnover markers. This secondary analysis examined the effect of 12 weeks of TRE vs. unrestricted eating on bone turnover and BMD. Overweight and obese adults aged 18-65 y (n = 20) were randomized to TRE (ad libitum 8-h eating window) or non-TRE. Serum N-terminal propeptide of type I collagen (P1NP), cross-linked N-telopeptide of type I collagen (NTX), and parathyroid hormone (PTH) levels were measured and dual-energy X-ray absorptiometry (DXA) scans were taken pre- and post-intervention. In both groups, P1NP decreased significantly (p = 0.04) but trended to a greater decrease in the non-TRE group (p = 0.07). The treatment time interaction for bone mineral content (BMC) was significant (p = 0.02), such that BMC increased in the TRE group and decreased in the non-TRE group. Change in P1NP was inversely correlated with change in weight (p = 0.04) overall, but not within each group. These findings suggest that TRE does not adversely affect bone over a moderate timeframe. Further research should examine the long-term effects of TRE on bone.

Lipophagy-derived fatty acids undergo extracellular efflux via lysosomal exocytosis.

The autophagic degradation of lipid droplets (LDs), termed lipophagy, is a major mechanism that contributes to lipid turnover in numerous cell types. While numerous factors, including nutrient deprivation or overexpression of PNPLA2/ATGL (patatin-like phospholipase domain containing 2) drive lipophagy, the trafficking of fatty acids (FAs) produced from this pathway is largely unknown. Herein, we show that PNPLA2 and nutrient deprivation promoted the extracellular efflux of FAs. Inhibition of autophagy or lysosomal lipid degradation attenuated FA efflux highlighting a critical role for lipophagy in this process. Rather than direct transport of FAs across the lysosomal membrane, lipophagy-derived FA efflux requires lysosomal fusion to the plasma membrane. The lysosomal Ca2+ channel protein MCOLN1/TRPML1 (mucolipin 1) regulates lysosomal-plasma membrane fusion and its overexpression increased, while inhibition blocked FA efflux. In addition, inhibition of autophagy/lipophagy or MCOLN1, or sequestration of extracellular FAs with BSA attenuated the oxidation and re-esterification of lipophagy-derived FAs. Overall, these studies show that the well-established pathway of lysosomal fusion to the plasma membrane is the primary route for the disposal of FAs derived from lipophagy. Moreover, the efflux of FAs and their reuptake or subsequent extracellular trafficking to adjacent cells may play an important role in cell-to-cell lipid exchange and signaling.Abbreviations: ACTB: beta actin; ADRA1A: adrenergic receptor alpha, 1a; ALB: albumin; ATG5: autophagy related 5; ATG7: autophagy related 7; BafA1: bafilomycin A1; BECN1: beclin 1; BHBA: beta-hydroxybutyrate; BSA: bovine serum albumin; CDH1: e-cadherin; CQ: chloroquine; CTSB: cathepsin B; DGAT: diacylglycerol O-acyltransferase; FA: fatty acid; HFD: high-fat diet; LAMP1: lysosomal-associated membrane protein 1; LD: lipid droplet; LIPA/LAL: lysosomal acid lipase A; LLME: Leu-Leu methyl ester hydrobromide; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MCOLN1/TRPML1: mucolipin 1; MEF: mouse embryo fibroblast; PBS: phosphate-buffered saline; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PLIN: perilipin; PNPLA2/ATGL patatin-like phospholipase domain containing 2; RUBCN (rubicon autophagy regulator); SM: sphingomyelin; TAG: triacylglycerol; TMEM192: transmembrane protein 192; VLDL: very low density lipoprotein.

Hepatic lipid droplets: A balancing act between energy storage and metabolic dysfunction in NAFLD.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is defined by the abundance of lipid droplets (LDs) in hepatocytes. While historically considered simply depots for energy storage, LDs are increasingly recognized to impact a wide range of biological processes that influence cellular metabolism, signaling, and function. While progress has been made toward understanding the factors leading to LD accumulation (i.e. steatosis) and its progression to advanced stages of NAFLD and/or systemic metabolic dysfunction, much remains to be resolved. SCOPE OF REVIEW: This review covers many facets of LD biology. We provide a brief overview of the major pathways of lipid accretion and degradation that contribute to steatosis and how they are altered in NAFLD. The major focus is on the relationship between LDs and cell function and the detailed mechanisms that couple or uncouple steatosis from the severity and progression of NAFLD and systemic comorbidities. The importance of specific lipids and proteins within or on LDs as key components that determine whether LD accumulation is linked to cellular and metabolic dysfunction is presented. We discuss emerging areas of LD biology and future research directions that are needed to advance our understanding of the role of LDs in NAFLD etiology. MAJOR CONCLUSIONS: Impairments in LD breakdown appear to contribute to disease progression, but inefficient incorporation of fatty acids (FAs) into LD-containing triacylglycerol (TAG) and the consequential changes in FA partitioning also affect NAFLD etiology. Increased LD abundance in hepatocytes does not necessarily equate to cellular dysfunction. While LD accumulation is the prerequisite step for most NAFLD cases, the protein and lipid composition of LDs are critical factors in determining the progression from simple steatosis. Further defining the detailed molecular mechanisms linking LDs to metabolic dysfunction is important for designing effective therapeutic approaches targeting NAFLD and its comorbidities.

Time-Restricted Eating Alters Food Intake Patterns, as Prospectively Documented by a Smartphone Application.

Time-restricted eating (TRE) can facilitate weight loss, yet its effect on eating patterns remains unknown. Twenty adults with BMI ≥ 25 kg/m2 underwent a 12-week randomized trial, examining the effect of an 8-h, time-restricted eating intervention on dietary patterns. Oral intake was documented using a smartphone. Dietary patterns, assessed as frequency of eating occasions (EOs) and types of meals/snacks and beverages, were compared between baseline (T0), early-intervention (T1), and end-intervention (T2). At T1 and T2, both groups had less EOs compared to T0, with greater reduction seen in the TRE group (-28%) than the non-TRE group (-12%) at T2 (p = 0.01 vs. non-TRE). Comparing T1 to T0, the TRE group documented less incomplete meals (-32.5%: p = 0.02), high quality snacks (-23.6%: p = 0.03), and low quality snacks (-36.6%: p = 0.004). Comparing T2 to T0, the TRE group documented less incomplete meals (-33.9%: p = 0.03), high quality snacks (-28.1%: p < 0.001) and low quality snacks (-51.2%: p < 0.001). Caffeinated beverage intake was reduced in the TRE group at T1 (-20.2%) and T2 (-28.8%) vs. T0, but remained unaltered in the non-TRE group. By using a smartphone application to document dietary intake, TRE significantly reduced the number of EOs, snacks, and caffeinated beverages, relative to baseline and relative to the non-TRE.

Regulation of Metabolic Homeostasis in Cell Culture Bioprocesses.

Mammalian cells are the main tool for the production of therapeutic proteins, viruses for gene therapy, and cells for cell therapy. In production processes cell metabolism is the main driver that causes changes in the growth environment and affects productivity and product quality. Of all nutrients, glucose has the most prominent impact on bioprocesses. We summarize recent findings on the regulation of glucose and energy metabolism in cultured cells. Local allosteric regulations and post-translational modifications of enzymes in metabolic networks interplay with global signaling and transcriptional regulation. These regulatory networks sustain homeostasis across the cytosolic and mitochondrial compartments. Understanding the regulation of glucose metabolism and metabolic state is crucial for enhancing process productivity and product quality.