Lipid droplet targeting of ABHD5 and PNPLA3 I148M is required to promote liver steatosis.

The storage and release of triacylglycerol (TAG) in lipid droplets (LDs) is regulated by dynamic protein interactions. α/β hydrolase domain-containing protein 5 (ABHD5; also known as CGI-58) is a membrane/LD bound protein that functions as a co-activator of Patatin Like Phospholipase Domain Containing 2 (PNPLA2; also known as Adipose triglyceride lipase, ATGL) the rate-limiting enzyme for TAG hydrolysis. The dysregulation of TAG hydrolysis is involved in various metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD).

Choline-deficient, high-fat diet-induced MASH in Göttingen Minipigs: characterization and effects of a chow reversal period.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) is increasing, and translational animal models are needed to develop novel treatments for this disease. The physiology and metabolism of pigs have a relatively high resemblance to humans, and the present study aimed to characterize choline-deficient and high-fat diet (CDAHFD)-fed Göttingen Minipigs as a novel animal model of MASLD/MASH. Göttingen Minipigs were fed CDAHFD for up to 5 mo, and the phenotype was investigated by the analysis of plasma parameters and repeated collection of liver biopsies.

An unbiased ranking of murine dietary models based on their proximity to human metabolic dysfunction-associated steatotic liver disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, encompasses steatosis and metabolic dysfunction-associated steatohepatitis (MASH), leading to cirrhosis and hepatocellular carcinoma. Preclinical MASLD research is mainly performed in rodents; however, the model that best recapitulates human disease is yet to be defined. We conducted a wide-ranging retrospective review (metabolic phenotype, liver histopathology, transcriptome benchmarked against humans) of murine models (mostly male) and ranked them using an unbiased MASLD 'human proximity score' to define their metabolic relevance and ability to induce MASH-fibrosis.

Fibroblast growth factor-21 improves insulin action in nonlactating ewes.

During metabolically demanding physiological states, ruminants and other mammals coordinate nutrient use among tissues by varying the set point of insulin action. This set point is regulated in part by metabolic hormones with some antagonizing (e.g.

The anti-obesity effect of FGF19 does not require UCP1-dependent thermogenesis.

Objective: Fibroblast growth factor 19 (FGF19) is a postprandial hormone which plays diverse roles in the regulation of bile acid, glucose, and lipid metabolism. Administration of FGF19 to obese/diabetic mice lowers body weight, improves insulin sensitivity, and enhances glycemic control. The primary target organ of FGF19 is the liver, where it regulates bile acid homeostasis in response to nutrient absorption.

Fibroblast growth factor-21 (FGF21) administration to early-lactating dairy cows. II. Pharmacokinetics, whole-animal performance, and lipid metabolism.

Dairy cows cope with severe energy insufficiency in early lactation by engaging in intense and sustained mobilization of fatty acids from adipose tissue. An unwanted side effect of this adaptation is excessive lipid accumulation in the liver, which in turn impairs hepatic functions. Mice experiencing increased hepatic fatty acid flux are protected from this condition through coordinated actions of the newly described hormone fibroblast growth factor-21 (FGF21) on liver and adipose tissue.

Fibroblast growth factor-21 (FGF21) administration to early-lactating dairy cows. I. Effects on signaling and indices of insulin action.

Modern dairy cows rely on hormonally driven mechanisms to coordinate the metabolic adaptations needed to meet the energy and nutrient deficits of early lactation. In the case of glucose, dairy cows cope with its scarcity during early lactation via reduced plasma concentrations of insulin and the insulin sensitizing hormone adiponectin and increased insulin resistance. Reduced insulin action promotes diversion of available glucose to the mammary gland but increases susceptibility to diseases if excessive.

Effects of heat stress and insulin sensitizers on pig adipose tissue.

Heat stress (HS) negatively impacts several swine production variables, including carcass fat quality and quantity. Pigs reared in HS have more adipose tissue than energetically predicted, explainable, in part, by HS-induced hyperinsulinemia. Study objectives were to evaluate insulin's role in altering fat characteristics during HS via feeding insulin-sensitizing compounds.

Fibroblast growth factor 21 increases hepatic oxidative capacity but not physical activity or energy expenditure in hepatic peroxisome proliferator-activated receptor γ coactivator-1α-deficient mice.

New Findings: What is the central question of this study? Does a reduction in hepatic peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), which has been observed in an insulin-resistant obese state, impair the ability of fibroblast growth factor 21 (FGF21) to modulate metabolism? What is the main finding and its importance? A deficit in hepatic PGC-1α does not compromise the ability of FGF21 to increase hepatic fatty acid oxidation; however, the effects of FGF21 to regulate whole-body metabolism (i.e. total and resting energy expenditure), as well as ambulatory activity, were altered when hepatic PGC-1α was reduced.

FGF21 Is an Insulin-Dependent Postprandial Hormone in Adult Humans.

Context: Fibroblast growth factor 21 (FGF21) secretion has been shown to respond directly to carbohydrate consumption, with glucose, fructose, and sucrose all reported to increase plasma levels of FGF21 in rodents and humans. However, carbohydrate consumption also results in secretion of insulin.

Objective: The aim of this study was to examine the combined and independent effects of hyperglycemia and hyperinsulinemia on total and bioactive FGF21 in the postprandial period in humans, and determine whether this effect is attenuated in conditions of altered insulin secretion and action.

High-fat, high-fructose, high-cholesterol feeding causes severe NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine.

Pediatric obesity and nonalcoholic steatohepatitis (NASH) are on the rise in industrialized countries, yet our ability to mechanistically examine this relationship is limited by the lack of a suitable higher animal models. Here, we examined the effects of high-fat, high-fructose corn syrup, high-cholesterol Western-style diet (WD)-induced obesity on NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine. Juvenile female Ossabaw swine (5 wk old) were fed WD (43.

Effect of circulating glucagon and free fatty acids on hepatic FGF21 production in dairy cows.

Modern dairy cows meet the energy demand of early lactation by calling on hormonally driven mechanisms to increase the use of lipid reserves. In this context, we recently reported that fibroblast growth factor-21 (FGF21), a hormone required for efficient use of lipid reserves in rodents, is upregulated in periparturient dairy cows. Increased plasma FGF21 in early lactation coincides with elevated circulating concentrations of glucagon (GCG) and nonesterified fatty acids (NEFA).

Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21.

Exercise enhances insulin sensitivity; it also improves adipocyte metabolism and reduces adipose tissue inflammation through poorly defined mechanisms. Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone-like protein whose insulin-sensitizing properties are predominantly mediated via receptor signaling in adipose tissue (AT). Recently, FGF21 has also been demonstrated to have anti-inflammatory properties.

Transcriptomic differences in intra-abdominal adipose tissue in extremely obese adolescents with different stages of NAFLD.

Mechanisms responsible for progression of nonalcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH) remain poorly defined. To examine the potential contribution of adipose tissue to NAFLD progression, we performed a complete transcriptomic analysis using RNA sequencing (RNA-Seq) on intra-abdominal adipose tissue (IAT) from severely obese adolescents [M 16.9 ± 0.

Fibroblast growth factor 21 and exercise-induced hepatic mitochondrial adaptations.

Exercise stimulates hepatic mitochondrial adaptations; however, the mechanisms remain largely unknown. Here we tested whether FGF21 plays an obligatory role in exercise induced hepatic mitochondrial adaptations by testing exercise responses in FGF21 knockout mice. FGF21 knockout (FGF21-KO) and wild-type (WT) mice (11-12 wk of age) had access to voluntary running wheels for exercise (EX) or remained sedentary for 8 wk.

Discrete Aspects of FGF21 In Vivo Pharmacology Do Not Require UCP1.

A primary target of the pleiotropic metabolic hormone FGF21 is adipose tissue, where it initiates a gene expression program to enhance energy expenditure, an effect presumed to be centered on augmented UCP1 expression and activity. In UCP1 null (UCP1KO) mice, we show that the effect of FGF21 to increase the metabolic rate is abolished. However, in contrast to prior expectations, we found that increased UCP1-dependent thermogenesis is only partially required to achieve the beneficial effects of FGF21 treatment.

Fibroblast growth factor 21 analogue LY2405319 lowers blood glucose in streptozotocin-induced insulin-deficient diabetic mice by restoring brown adipose tissue function.

Aim: To investigate the effects of LY2405319, an analogue of fibroblast growth factor 21 (FGF21), on glucose homeostasis in streptozotocin (STZ)-induced insulin-deficient mice (STZ mice).

Methods: Nine-week-old male C57BL/6J mice were administered a single intraperitoneal injection of STZ (150 mg/kg). One week later, after confirmation of hyperglycaemia, saline or LY2405319 (5 mg/kg) was injected subcutaneously daily for 4 weeks.

Unique transcriptomic signature of omental adipose tissue in Ossabaw swine: a model of childhood obesity.

To better understand the impact of childhood obesity on intra-abdominal adipose tissue phenotype, a complete transcriptomic analysis using deep RNA-sequencing (RNA-seq) was performed on omental adipose tissue (OMAT) obtained from lean and Western diet-induced obese juvenile Ossabaw swine. Obese animals had 88% greater body mass, 49% greater body fat content, and a 60% increase in OMAT adipocyte area (all P < 0.05) compared with lean pigs.

Diet-induced obesity alters immune cell infiltration and expression of inflammatory cytokine genes in mouse ovarian and peri-ovarian adipose depot tissues.

Dysregulation of immune cells and/or altered inflammatory signaling have been implicated with reproductive dysfunction. Physiological changes leading to perturbations in the profile of immune cells and/or pro-inflammatory cytokines in or around female reproductive tissue could potentially have profound effects on ovarian function. Obesity is associated with chronic low-grade inflammation due, in part, to increased immune cell infiltration and inflammation in visceral adipose depots.

High fat diet induced obesity alters ovarian phosphatidylinositol-3 kinase signaling gene expression.

Insulin regulates ovarian phosphatidylinositol-3-kinase (PI3 K) signaling, important for primordial follicle viability and growth activation. This study investigated diet-induced obesity impacts on: (1) insulin receptor (Insr) and insulin receptor substrate 1 (Irs1); (2) PI3K components (Kit ligand (Kitlg), kit (c-Kit), protein kinase B alpha (Akt1) and forkhead transcription factor subfamily 3 (Foxo3a)); (3) xenobiotic biotransformation (microsomal epoxide hydrolase (Ephx1), Cytochrome P450 isoform 2E1 (Cyp2e1), Glutathione S-transferase (Gst) isoforms mu (Gstm) and pi (Gstp)) and (4) microRNA's 184, 205, 103 and 21 gene expression. INSR, GSTM and GSTP protein levels were also measured.

Vascular transcriptional alterations produced by juvenile obesity in Ossabaw swine.

We adopted a transcriptome-wide microarray analysis approach to determine the extent to which vascular gene expression is altered as a result of juvenile obesity and identify obesity-responsive mRNAs. We examined transcriptional profiles in the left anterior descending coronary artery (LAD), perivascular fat adjacent to the LAD, and descending thoracic aorta between obese (n = 5) and lean (n = 6) juvenile Ossabaw pigs (age = 22 wk). Obesity was experimentally induced by feeding the animals a high-fat/high-fructose corn syrup/high-cholesterol diet for 16 wk.

Sterculic oil, a natural inhibitor of SCD1, improves the metabolic state of obese OLETF rats.

Objective: Abnormal lipid metabolism and excess accumulation of lipid in non-adipose tissues are defining characteristics of obesity and its comorbidities. Expression and/or activity of stearoyl-CoA desaturase-1 (SCD1), a major regulator of lipid metabolism, is increased with obesity and the reduction/ablation of this enzyme is associated with an improved metabolic profile. Sterculic oil (SO), obtained from the seeds of the Sterculia feotida tree, contains a high concentration of cyclopropenoic fatty acids which are known inhibitors of SCD1.

Sterculic Oil, a Natural SCD1 Inhibitor, Improves Glucose Tolerance in Obese ob/ob Mice.

Obesity and its metabolic complications are associated with increased expression/activity of stearoyl-CoA desaturase-1 (SCD1), a major regulator of lipid metabolism. Reduction or ablation of this enzyme is associated with an improved metabolic profile and has gained attention as a target for pharmaceutical development. Sterculic oil (SO) is a known inhibitor of SCD1 and may provide a natural approach for treating obesity and/or insulin resistance.