Björn Morén
Apr 15, 2020; 0:jlr.ILR120000808v1-jlr.ILR120000808
Images in Lipid Research

Stimulating brown adipose tissue (BAT) activity represents a promising therapy for overcoming metabolic diseases. mTORC2 is important for regulating BAT metabolism, but its downstream targets have not been fully characterized. In this study, we apply proteomics and phosphoproteomics to investigate the downstream effectors of mTORC2 in brown adipocytes. We compare wild-type controls to isogenic cells with an induced knockout of the mTORC2 subunit RICTOR (Rictor-iKO) by stimulating each with insulin for a 30-minute time course. In Rictor-iKO cells, we identify decreases to the abundance of glycolytic and de novo lipogenesis enzymes, and increases to mitochondrial proteins as well as a set of proteins known to increase upon interferon stimulation. We also observe significant differences to basal phosphorylation due to chronic RICTOR loss including decreased phosphorylation of the lipid droplet protein perilipin-1 in Rictor-iKO cells, suggesting that RICTOR could be involved with regulating basal lipolysis or droplet dynamics. Finally, we observe mild dampening of acute insulin signaling response in Rictor-iKO cells, and a subset of AKT substrates exhibiting statistically significant dependence on RICTOR.

1 January 2007 , Number 2

For all the cynicism it has evoked, the United States’ Iraq Study Group report might still lead to a regional diplomatic process, which could ease Iran and the US into negotiations. A grand bargain is very unlikely, but with Washington at the table, there might be enough advantage for both sides in a gradual process to halt the current slide towards a deeper confrontation.

7 May 2020 , Volume 96, Number 3

Zinc metallopeptidase STE24 (ZMPSTE24) is essential for the conversion of farnesyl–prelamin A to mature lamin A, a key component of the nuclear lamina. In the absence of ZMPSTE24, farnesyl–prelamin A accumulates in the nucleus and exerts toxicity, causing a variety of disease phenotypes. By ~4 months of age, both male and female Zmpste24^–/– mice manifest a near-complete loss of adipose tissue, but it has never been clear whether this phenotype is a direct consequence of farnesyl–prelamin A toxicity in adipocytes. To address this question, we generated a conditional knockout Zmpste24 allele and used it to create adipocyte-specific Zmpste24–knockout mice. To boost farnesyl–prelamin A levels, we bred in the "prelamin A–only" Lmna allele. Gene expression, immunoblotting, and immunohistochemistry experiments revealed that adipose tissue in these mice had decreased Zmpste24 expression along with strikingly increased accumulation of prelamin A. In male mice, Zmpste24 deficiency in adipocytes was accompanied by modest changes in adipose stores (an 11% decrease in body weight, a 23% decrease in body fat mass, and significantly smaller gonadal and inguinal white adipose depots). No changes in adipose stores were detected in female mice, likely because prelamin A expression in adipose tissue is lower in female mice. Zmpste24 deficiency in adipocytes did not alter the number of macrophages in adipose tissue, nor did it alter plasma levels of glucose, triglycerides, or fatty acids. We conclude that ZMPSTE24 deficiency in adipocytes, and the accompanying accumulation of farnesyl–prelamin A, reduces adipose tissue stores, but only modestly and only in male mice.

Lipid droplets (LDs) are frequently increased when excessive lipid accumulation leads to cellular dysfunction. Distinct from mouse beta cells, LDs are prominent in human beta cells, however, the regulation of LD mobilization (lipolysis) in human beta cells remains unclear. We found that glucose increases lipolysis in non-diabetic human islets, but not in type 2 diabetic (T2D) islets, indicating dysregulation of lipolysis in T2D islets. Silencing adipose triglyceride lipase (ATGL) in human pseudoislets (shATGL) increased triglycerides, and the number and size of LDs indicating that ATGL is the principal lipase in human beta cells. In shATGL pseudoislets, biphasic glucose-stimulated insulin secretion (GSIS) and insulin secretion to IBMX and KCl were all reduced without altering oxygen consumption rate compared with scramble control. Like human islets, INS1 cells showed visible LDs, glucose responsive lipolysis, and impairment of GSIS after ATGL silencing. ATGL deficient INS1 cells and human pseudoislets showed reduced Stx1a, a key SNARE component. Proteasomal degradation of Stx1a was accelerated likely through reduced palmitoylation in ATGL deficient INS1 cells. Therefore, ATGL is responsible for LD mobilization in human beta cells and supports insulin secretion by stabilizing Stx1a. The dysregulated lipolysis may contribute to LD accumulation and beta cell dysfunction in T2D islets.

Lipid droplets (LDs) are frequently increased when excessive lipid accumulation leads to cellular dysfunction. Distinct from mouse beta cells, LDs are prominent in human beta cells, however, the regulation of LD mobilization (lipolysis) in human beta cells remains unclear. We found that glucose increases lipolysis in non-diabetic human islets, but not in type 2 diabetic (T2D) islets, indicating dysregulation of lipolysis in T2D islets. Silencing adipose triglyceride lipase (ATGL) in human pseudoislets (shATGL) increased triglycerides, and the number and size of LDs indicating that ATGL is the principal lipase in human beta cells. In shATGL pseudoislets, biphasic glucose-stimulated insulin secretion (GSIS) and insulin secretion to IBMX and KCl were all reduced without altering oxygen consumption rate compared with scramble control. Like human islets, INS1 cells showed visible LDs, glucose responsive lipolysis, and impairment of GSIS after ATGL silencing. ATGL deficient INS1 cells and human pseudoislets showed reduced Stx1a, a key SNARE component. Proteasomal degradation of Stx1a was accelerated likely through reduced palmitoylation in ATGL deficient INS1 cells. Therefore, ATGL is responsible for LD mobilization in human beta cells and supports insulin secretion by stabilizing Stx1a. The dysregulated lipolysis may contribute to LD accumulation and beta cell dysfunction in T2D islets.

Obesity has recently become a prevalent health threat worldwide. Although emerging evidence has suggested a strong link between the pentose phosphate pathway (PPP) and obesity, the role of transketolase (TKT), an enzyme in the non-oxidative branch of the PPP which connects PPP and glycolysis, remains obscure in adipose tissues. In this study, we specifically delete TKT in mouse adipocytes and find no obvious phenotype upon normal diet feeding. However, adipocyte TKT abrogation attenuates high fat diet (HFD)-induced obesity, reduces hepatic steatosis, improves glucose tolerance, alleviates insulin resistance and increases energy expenditure. Mechanistically, TKT deficiency accumulates non-oxidative PPP metabolites, decreases glycolysis and pyruvate input into the mitochondria, leading to increased lipolytic enzyme gene expression and enhanced lipolysis, fatty acid oxidation and mitochondrial respiration. Therefore, our data not only identify a novel role of TKT in regulating lipolysis and obesity, but also suggest limiting glucose-derived carbon into the mitochondria induces lipid catabolism and energy expenditure.

Accumulating evidence suggests that brown adipose tissue (BAT) is a potential therapeutic target for managing obesity and related diseases. PGAM family member 5, mitochondrial serine/threonine protein phosphatase (PGAM5), is a protein phosphatase that resides in the mitochondria and regulates many biological processes, including cell death, mitophagy, and immune responses. Because BAT is a mitochondria-rich tissue, we have hypothesized that PGAM5 has a physiological function in BAT. We previously reported that PGAM5-knockout (KO) mice are resistant to severe metabolic stress. Importantly, lipid accumulation is suppressed in PGAM5-KO BAT, even under unstressed conditions, raising the possibility that PGAM5 deficiency stimulates lipid consumption. However, the mechanism underlying this observation is undetermined. Here, using an array of biochemical approaches, including quantitative RT-PCR, immunoblotting, and oxygen consumption assays, we show that PGAM5 negatively regulates energy expenditure in brown adipocytes. We found that PGAM5-KO brown adipocytes have an enhanced oxygen consumption rate and increased expression of uncoupling protein 1 (UCP1), a protein that increases energy consumption in the mitochondria. Mechanistically, we found that PGAM5 phosphatase activity and intramembrane cleavage are required for suppression of UCP1 activity. Furthermore, utilizing a genome-wide siRNA screen in HeLa cells to search for regulators of PGAM5 cleavage, we identified a set of candidate genes, including phosphatidylserine decarboxylase (PISD), which catalyzes the formation of phosphatidylethanolamine at the mitochondrial membrane. Taken together, these results indicate that PGAM5 suppresses mitochondrial energy expenditure by down-regulating UCP1 expression in brown adipocytes and that its phosphatase activity and intramembrane cleavage are required for UCP1 suppression.

Luigi Fontana
Apr 1, 2007; 56:1010-1013
Metabolism

The whitening and loss of brown adipose tissue (BAT) during obesity and aging promote metabolic disorders and related diseases. The imbalance of Ca²⁺ homeostasis accounts for the dysfunction and clearance of mitochondria during BAT whitening. Capsaicin, a dietary factor activating TRPV1, can inhibit obesity induced by high-fat diet (HFD), but whether capsaicin inhibits BAT loss and the underlying mechanism remain unclear. In this study, we determined that the inhibitory effects of capsaicin on HFD-induced obesity and BAT whitening were dependent on the participation of SIRT3, a critical mitochondrial deacetylase. SIRT3 also mediated all of the beneficial effects of capsaicin on alleviating reactive oxygen species generation, elevating mitochondrial activity, and restricting mitochondrial calcium overload induced by HFD. Mechanistically, SIRT3 inhibits mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium overload by reducing the H3K27ac level on the MCU promoter in an AMPK-dependent manner. In addition, HFD also inhibits AMPK activity to reduce SIRT3 expression, which could be reversed by capsaicin. Capsaicin intervention also inhibited aging-induced BAT whitening through this mechanism. In conclusion, this study emphasizes a critical role of the AMPK/SIRT3 pathway in the maintenance of BAT morphology and function and suggests that intervention in this pathway may be an effective target for preventing obesity- or age-related metabolic diseases.

Adipose tissue macrophages (ATMs) are involved in the development of insulin resistance in obesity. We have recently shown that myeloid cell–specific reduction of HMG-CoA reductase (Hmgcr^m–/m–), which is the rate-limiting enzyme in cholesterol biosynthesis, protects against atherosclerosis by inhibiting macrophage migration in mice. We hypothesized that ATMs are harder to accumulate in Hmgcr^m–/m– mice than in control Hmgcr^fl/fl mice in the setting of obesity. To test this hypothesis, we fed Hmgcr^m–/m– and Hmgcr^fl/fl mice a high-fat diet (HFD) for 24 weeks and compared plasma glucose metabolism as well as insulin signaling and histology between the two groups. Myeloid cell–specific reduction of Hmgcr improved glucose tolerance and insulin sensitivity without altering body weight in the HFD-induced obese mice. The improvement was due to a decrease in the number of ATMs. The ATMs were reduced by decreased recruitment of macrophages as a result of their impaired chemotactic activity. These changes were associated with decreased expression of proinflammatory cytokines in adipose tissues. Myeloid cell–specific reduction of Hmgcr also attenuated hepatic steatosis. In conclusion, reducing myeloid HMGCR may be a promising strategy to improve insulin resistance and hepatic steatosis in obesity.

Joseph G. Yu
Oct 1, 2002; 51:2968-2974
Obesity Studies

Masayuki Saito
Jul 1, 2009; 58:1526-1531
Metabolism

Norikazu Maeda
Sep 1, 2001; 50:2094-2099
Pathophysiology

BM Spiegelman
Apr 1, 1998; 47:507-514
Articles

Incretin hormone dysregulation contributes to reduced insulin secretion and hyperglycemia in patients with type 2 diabetes mellitus (T2DM). Resistance to glucose-dependent insulinotropic polypeptide (GIP) action may occur through desensitization or downregulation of β-cell GIP receptors (GIP-R). Studies in rodents and cell lines show GIP-R expression can be regulated through peroxisome proliferator–activated receptor (PPAR) response elements (PPREs). Whether this occurs in humans is unknown. To test this, we conducted a randomized, double-blind, placebo-controlled trial of pioglitazone therapy on GIP-mediated insulin secretion and adipocyte GIP-R expression in subjects with well-controlled T2DM. Insulin sensitivity improved, but the insulinotropic effect of infused GIP was unchanged following 12 weeks of pioglitazone treatment. In parallel, we observed increased GIP-R mRNA expression in subcutaneous abdominal adipocytes from subjects treated with pioglitazone. Treatment of cultured human adipocytes with troglitazone increased PPAR binding to GIP-R PPREs. These results show PPAR agonists regulate GIP-R expression through PPREs in human adipocytes, but suggest this mechanism is not important for regulation of the insulinotropic effect of GIP in subjects with T2DM. Because GIP has antilipolytic and lipogenic effects in adipocytes, the increased GIP-R expression may mediate accretion of fat in patients with T2DM treated with PPAR agonists.

The BMP2/4 antagonist and novel adipokine Gremlin 1 is highly expressed in human adipose cells and increased in hypertrophic obesity. As a secreted antagonist, it inhibits the effect of BMP2/4 on adipose precursor cell commitment/differentiation. We examined mRNA levels of Gremlin 1 in key target tissues for insulin and also measured tissue and serum levels in several carefully phenotyped human cohorts. Gremlin 1 expression was high in adipose tissue, higher in visceral than in subcutaneous tissue, increased in obesity, and further increased in type 2 diabetes (T2D). A similar high expression was seen in liver biopsies, but expression was considerably lower in skeletal muscles. Serum levels were increased in obesity but most prominently in T2D. Transcriptional activation in both adipose tissue and liver as well as serum levels were strongly associated with markers of insulin resistance in vivo (euglycemic clamps and HOMA of insulin resistance), and the presence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We also found Gremlin 1 to antagonize insulin signaling and action in human primary adipocytes, skeletal muscle, and liver cells. Thus, Gremlin 1 is a novel secreted insulin antagonist and biomarker as well as a potential therapeutic target in obesity and its complications T2D and NAFLD/NASH.

Obesity-associated type 2 diabetes mellitus (T2DM) entails insulin resistance and loss of β-cell mass. Adipose tissue mitochondrial dysfunction is emerging as a key component in the etiology of T2DM. Identifying approaches to preserve mitochondrial function, adipose tissue integrity, and β-cell mass during obesity is a major challenge. Mitochondrial ferritin (FtMT) is a mitochondrial matrix protein that chelates iron. We sought to determine whether perturbation of adipocyte mitochondria influences energy metabolism during obesity. We used an adipocyte-specific doxycycline-inducible mouse model of FtMT overexpression (FtMT-Adip mice). During a dietary challenge, FtMT-Adip mice are leaner but exhibit glucose intolerance, low adiponectin levels, increased reactive oxygen species damage, and elevated GDF15 and FGF21 levels, indicating metabolically dysfunctional fat. Paradoxically, despite harboring highly dysfunctional fat, transgenic mice display massive β-cell hyperplasia, reflecting a beneficial mitochondria-induced fat-to-pancreas interorgan signaling axis. This identifies the unique and critical impact that adipocyte mitochondrial dysfunction has on increasing β-cell mass during obesity-related insulin resistance.

Branched esters of palmitic acid and hydroxystearic acid (PAHSA) are anti-inflammatory and antidiabetic lipokines that connect glucose and lipid metabolism. We aimed to characterize involvement of the 5-PAHSA regioisomer in the adaptive metabolic response of white adipose tissue (WAT) to cold exposure (CE) in mice, exploring the cross talk between glucose utilization and lipid metabolism. CE promoted local production of 5- and 9-PAHSAs in WAT. Metabolic labeling of de novo lipogenesis (DNL) using ²H₂O revealed that 5-PAHSA potentiated the effects of CE and stimulated triacylglycerol (TAG)/fatty acid (FA) cycling in WAT through impacting lipogenesis and lipolysis. Adipocyte lipolytic products were altered by 5-PAHSA through selective FA re-esterification. The impaired lipolysis in global adipose triglyceride lipase (ATGL) knockout mice reduced free PAHSA levels and uncovered a metabolite reservoir of TAG-bound PAHSAs (TAG estolides) in WAT. Utilization of ¹³C isotope tracers and dynamic metabolomics documented that 5-PAHSA primes adipocytes for glucose metabolism in a different way from insulin, promoting DNL and impeding TAG synthesis. In summary, our data reveal new cellular and physiological mechanisms underlying the beneficial effects of 5-PAHSA and its relation to insulin action in adipocytes and independently confirm a PAHSA metabolite reservoir linked to ATGL-mediated lipolysis.

Insulin-mediated microvascular recruitment (IMVR) regulates delivery of insulin and glucose to insulin-sensitive tissues. We have previously proposed that perivascular adipose tissue (PVAT) controls vascular function through outside-to-inside communication and through vessel-to-vessel, or "vasocrine," signaling. However, direct experimental evidence supporting a role of local PVAT in regulating IMVR and insulin sensitivity in vivo is lacking. Here, we studied muscles with and without PVAT in mice using combined contrast-enhanced ultrasonography and intravital microscopy to measure IMVR and gracilis artery diameter at baseline and during the hyperinsulinemic-euglycemic clamp. We show, using microsurgical removal of PVAT from the muscle microcirculation, that local PVAT depots regulate insulin-stimulated muscle perfusion and glucose uptake in vivo. We discovered direct microvascular connections between PVAT and the distal muscle microcirculation, or adipomuscular arterioles, the removal of which abolished IMVR. Local removal of intramuscular PVAT altered protein clusters in the connected muscle, including upregulation of a cluster featuring Hsp90ab1 and Hsp70 and downregulation of a cluster of mitochondrial protein components of complexes III, IV, and V. These data highlight the importance of PVAT in vascular and metabolic physiology and are likely relevant for obesity and diabetes.

Reduced storage of dietary fatty acids (DFAs) in abdominal adipose tissues with enhanced cardiac partitioning has been shown in subjects with type 2 diabetes (T2D) and prediabetes. We measured DFA metabolism and organ partitioning using positron emission tomography with oral and intravenous long-chain fatty acid and glucose tracers during a standard liquid meal in 12 obese subjects with T2D before and 8–12 days after bariatric surgery (sleeve gastrectomy or sleeve gastrectomy and biliopancreatic diversion with duodenal switch). Bariatric surgery reduced cardiac DFA uptake from a median (standard uptake value [SUV]) 1.75 (interquartile range 1.39–2.57) before to 1.09 (1.04–1.53) after surgery (P = 0.01) and systemic DFA spillover from 56.7 mmol before to 24.7 mmol over 6 h after meal intake after surgery (P = 0.01), with a significant increase in intra-abdominal adipose tissue DFA uptake from 0.15 (0.04–0.31] before to 0.49 (0.20–0.59) SUV after surgery (P = 0.008). Hepatic insulin resistance was significantly reduced in close association with increased DFA storage in intra-abdominal adipose tissues (r = –0.79, P = 0.05) and reduced DFA spillover (r = 0.76, P = 0.01). We conclude that bariatric surgery in subjects with T2D rapidly reduces cardiac DFA partitioning and hepatic insulin resistance at least in part through increased intra-abdominal DFA storage and reduced spillover.

Invitation Only Research Event

HE Raffaele Trombetta, Italian Ambassador to the UK, Co-Host, COP 26
Archie Young, UK Lead Climate Negotiator, Cabinet Office 
Peter Betts, Associate Fellow, Energy, Environment and Resources Department, Chatham House
Chair: Professor Tim Benton, Research Director, Energy, Environment and Resources, Chatham House  

In the run-up to COP26 in Glasgow, Chatham House is organizing monthly briefings about the UN climate negotiations and climate change more broadly. The events provide an excellent opportunity to discuss the most pressing and complex climate issues of the day with government officials, renowned experts and members of the London-based diplomatic community.

Research Event

Event participants

Research Event

Event participants

500g cooked and peeled beetroot (about 900g fresh) 2 garlic cloves, crushed 1 red chilli, deseeded and finely chopped 1 cup of Greek yoghurt 5 fresh Medjool dates 3 tbsps. olive oil 1 tbsp. Za'atar Good pinch of Himalayan salt 2 shallots, finely sliced on the diagonal Handful of toasted and crushed hazelnuts 50g goat's cheese, crumbled

I seriously love cooking on the Weber more in winter cooler temperature make us feel more cosy and accentuate the taste buds and smell . Replaced the traditional peanuts with our wonderful local macadamias

chicken thigh fillets, skinless and cut in to finger length strips 100g melted butter 1 tbsp. native tomato spice mix plum and chilli bottled sauce

400g ripe roma (plum) or pomodorino (baby plum) tomatoes 1 1/2 tablespoons chopped mint 1 teaspoon dried oregano 90g plain flour 1 teaspoon baking powder 1 teaspoon salt Light olive oil, or sunflower oil for pan-frying 250g Greek-style yogurt 1 tablespoon finely chopped dill Lemon wedges, to serve

Jena : G. Fischer, 1901.

Frankfurt : Christian Winter, 1878.

Leipzig : F.C.W. Vogel, 1887.

Halle : M. Niemeyer, 1895.

Edinburgh : Oliver and Boyd, 1876.

London : Macmillan, 1891.

London : J. & A. Churchill, 1879.

London : H.K. Lewis, 1891.

Leipzig : Wilhelm Engelmann, 1897.

London : Swan Sonnenschein, 1898.

London (Old Bond Street) : published by John Warren ; [London] (Ave Maria Lane) : G & W.B. Whittaker, [between 1800 and 1899]

A new study ties the ousting of women directors, actors, producers and screenwriters to the rise of entertainment studios

Some epidemiologic evidence suggests an inverse association between sleep duration and obesity in various age groups. However, in the case of adolescents, inconsistent results have been reported, which can be partly explained by methodologic options.

Our study supports an effect of sleep duration in adiposity during adolescence and found gender differences in this association. The results are consistent by using either the traditional longitudinal approach or cross-lagged modeling. (Read the full article)

Obesity is associated with cardiometabolic risk factors and chronic conditions, such as type 2 diabetes. However, a proportion of overweight and obese youth remain free from cardiometabolic risk factors and are considered metabolically healthy.

This study provides insight into the determinants of cardiometabolic risk factors and the concept in health promotion of "fitness versus fatness." Hepatic lipid accumulation and not fitness level appears to drive cardiometabolic risk factor clustering among overweight and obese youth. (Read the full article)