No abstract

Lipid droplets (LDs) are intracellular organelles that store neutral lipids within cells. Over the last two decades there has been a dramatic growth in our understanding of LD biology and, in parallel, our understanding of the role of LDs in health and disease. In its simplest form, the LD regulates the storage and hydrolysis of neutral lipids, including triacylglycerol and/or cholesterol esters. It is becoming increasingly evident that alterations in the regulation of LD physiology and metabolism influence the risk of developing metabolic diseases such as diabetes. In this review we provide an update on the role of LD-associated proteins and LDs in metabolic disease. Overview of lipid dropletsLipid droplets (LDs) are intracellular organelles that store neutral lipids within cells. Over the last two decades there has been a dramatic growth in our understanding of LD biology and, in parallel, our understanding of the role they play in health and disease. LDs regulate the storage and hydrolysis of neutral lipids, including triacylglycerol (TAG) and/or cholesterol esters. For example, adipocytes, the major reservoir of TAG in the body, store their TAG within LDs, and TAG storage in adipocytes is increased in obese animals and humans. The rates of adipocyte lipolysis in many obese individuals are constitutively increased, resulting in elevated levels of circulating fatty acids, which may be stored as TAG in LDs within skeletal muscle and liver. Both local and circulating free fatty acids are thought to be important etiologic agents in the development of insulin resistance, hyperlipidemia, inflammation, and hepatic steatosis (1-3). In this article, we will briefly review the basic characteristics of LDs and then focus on our present knowledge of the current view of the role of LDs in metabolic disease.Cells have developed the capacity to store fatty acids as neutral lipids within LDs for several reasons. An important role of LDs in adipocytes is to store fatty acids as TAG to serve as a reservoir of energetic substrates that can be released when food is scarce. The detrimental effects associated with excess fatty acid entry into cells are often termed "lipotoxicity." Cells protect themselves from these effects by either oxidizing the fatty acids or sequestering them as TAG within LDs. Consistent with this hypothesis, activation of PPARα, which increases the expression of genes that encode oxidative proteins, also increases the expression of LDs and LD-associated proteins (4, 5). PPARγ and PPARδ, along with other transcription factors, can also promote droplet formation (4, 6). As noted above, when fatty acids exceed the oxidative capacity of cells, they not only enhance LD formation, but may also induce apoptosis. An example of the protection LD formation provides was demonstrated in an experiment in which exogenous oleic acid added to fibroblasts deficient in diacylglycerol acyltransferase 1 (DGAT1) promoted lipotoxic cell death. Expression of DGAT1, the terminal step in TAG synthesis, in fibroblasts channeled exces...

Objective: In contrast to intentionally restricting energy intake, restricting the eating window may be an option for treating obesity. By comparing time-restricted eating (TRE) with an unrestricted (non-TRE) control, it was hypothesized that TRE facilitates weight loss, alters body composition, and improves metabolic measures. Methods: Participants (17 women and 3 men; mean [SD]: 45.5 [12.1] years; BMI 34.1 [7.5] kg/m 2 ) with a prolonged eating window (15.4 [0.9] hours) were randomized to TRE (n = 11: 8-hour window, unrestricted eating within window) versus non-TRE (n = 9: unrestricted eating) for 12 weeks. Weight, body composition (dual x-ray absorptiometry), lipids, blood pressure, 2-hour oral glucose tolerance, 2-week continuous glucose monitoring, and 2-week physical activity (actigraphy assessed) were measured during the pre-and end-intervention periods. Results: The TRE group significantly reduced the eating window (endintervention window: 9.9 [2.0] hours) compared with the non-TRE group (end-intervention window: 15.1 [1.1] hours) (P < 0.01). Compared with non-TRE, TRE decreased the number of eating occasions, weight, lean mass, and visceral fat (all P ≤ 0.05). Compared with preintervention measures, the TRE group reduced the number of eating occasions (−21.9% [30.1%]) and reduced weight (−3.7% [1.8%]), fat mass (−4% [2.9%]), lean mass (−3.0% [2.7%]), and visceral fat (−11.1% [13.4%]) (all P ≤ 0.05). Physical activity and metabolic measures remained unchanged. Conclusions: In the setting of a randomized trial, TRE presents a simplified view of food intake that reduces weight.Obesity (2020) 28, 860-869.

Sixty-five Holstein cows were used to evaluate management schemes involving altered dry period (DP) lengths on subsequent milk production, energy balance (EB), and metabolic variables. Cows were assigned to one of 3 treatments: traditional 56-d DP (fed a low-energy diet from -56 to -29 d and a moderate energy diet from -28 d to parturition; T), 28-d DP (continuously fed a high energy diet; S), and no planned DP (continuously fed a high energy diet; N). Prepartum DM intake (DMI), measured from 56 d prepartum through parturition, was lower for cows on the T treatment than for cows on the S treatment and was higher for cows on the N treatment than for cows on the S treatment. There were no differences in prepartum plasma glucose, and beta-hydroxybutryric acid; there was a treatment by time interaction for prepartum plasma nonesterified fatty acid (NEFA). There was no difference in prepartum liver triglyceride (TG); postpartum liver TG was decreased for cows on the N treatment compared with cows on the S treatment, but was similar for cows on the T and S treatments. Postpartum NEFA was similar between cows on the T and S treatments, but was greater for cows on the S treatment than for cows on the N treatment. Postpartum glucose was greater for cows on the N treatment compared with cows on the S treatment and tended to be greater for cows on the S treatment than for cows on the T treatment. There was no difference in postpartum solids-corrected milk (SCM) production or DMI by cows on the T vs. S treatment. However, there was a tendency toward lower postpartum SCM production by cows on the N vs. S treatment and a tendency for greater postpartum DMI by cows on the N vs. S treatment. Postpartum EB was greater for cows on the S vs. T treatment and the N vs. S treatment. In general, T and S management schemes had similar effects on DMI, SCM, and metabolic variables in the first 70 d of the subsequent lactation. Eliminating the DP improved energy and metabolic status.

Despite advances in our understanding of the ways in which nutrient oversupply and triacylglycerol (TAG) anabolism contribute to hepatic steatosis, little is known about the lipases responsible for regulating hepatic TAG turnover. Recent studies have identified adipose triglyceride lipase (ATGL) as a major lipase in adipose tissue, although its role in the liver is largely unknown. Thus, we tested the contribution of ATGL to hepatic lipid metabolism and signaling. Adenovirus-mediated knockdown of hepatic ATGL resulted in steatosis in mice and decreased hydrolysis of TAG in primary hepatocyte cultures and in vitro assays. In addition to altering TAG hydrolysis, ATGL was shown to play a significant role in partitioning hydrolyzed fatty acids between metabolic pathways. Although ATGL gain and loss of function did not alter hepatic TAG secretion, fatty acid oxidation was increased by ATGL overexpression and decreased by ATGL knockdown. The effects on fatty acid oxidation coincided with decreased expression of peroxisome proliferator-activated receptor a (PPAR-a) and its target genes in mice with suppressed hepatic ATGL expression. However, PPAR-a agonism was unable to normalize the effects of ATGL knockdown on PPAR-a target gene expression, and this suggests that ATGL influences PPAR-a activity independently of ligandinduced activation. Conclusion: Taken together, these data show that ATGL is a major hepatic TAG lipase that plays an integral role in fatty acid partitioning and signaling to control energy metabolism. (HEPATOLOGY 2011;53:116-126)