Obesity-induced tissue alterations resist weight loss: A mechanistic review.

Interventions aimed at weight control often have limited effectiveness in combating obesity. This review explores how obesity-induced dysfunction in white (WAT) and brown adipose tissue (BAT), skeletal muscle, and the brain blunt weight loss, leading to retention of stored fat. In obesity, increased adrenergic stimulation and inflammation downregulate ß-adrenoreceptors and impair catecholaminergic signalling in adipocytes. This disrupts adrenergic-mediated lipolysis, diminishing lipid oxidation in both white and brown adipocytes, lowering thermogenesis and blunting fat loss. Emerging evidence suggests that WAT fibrosis is associated with worse weight loss outcomes; indeed, limiting collagen and laminin-α4 deposition mitigates WAT accumulation, enhances browning, and protects against high-fat-diet-induced obesity. Obesity compromises mitochondrial oxidative capacity and lipid oxidation in skeletal muscle, impairing its ability to switch between glucose and lipid metabolism in response to varying nutrient levels and exercise. This dysfunctional phenotype in muscle is exacerbated in the presence of obesity-associated sarcopenia. Additionally, obesity suppresses sarcolipin-induced sarcoplasmic reticulum calcium ATPase (SERCA) activation, resulting in reduced oxidative capacity, diminished energy expenditure, and increased adiposity. In the hypothalamus, obesity and overnutrition impair insulin and leptin signalling. This blunts central satiety signals, favouring a shift in energy balance toward energy conservation and body fat retention. Moreover, both obese animals and humans demonstrate impaired dopaminergic signalling and diminished responses to nutrient intake in the striatum, which tend to persist after weight loss. This may result in enduring inclinations toward overeating and a sedentary lifestyle. Collectively, the tissue adaptations described pose significant challenges to effectively achieving and sustaining weight loss in obesity.

Unexpected role for IGF-1 in starvation: Maintenance of blood glucose.

Wild-type (WT) mice maintain viable levels of blood glucose even when adipose stores are depleted by 6 d of 60% calorie restriction followed by a 23-h fast (hereafter designated as "starved" mice). Survival depends on ghrelin, an octanoylated peptide hormone. Mice that lack ghrelin suffer lethal hypoglycemia when subjected to the same starvation regimen. Ghrelin is known to stimulate secretion of growth hormone (GH), which in turn stimulates secretion of IGF-1 (insulin-like growth factor-1). In the current study, we found that starved ghrelin-deficient mice had a 90% reduction in plasma IGF-1 when compared with starved WT mice. Injection of IGF-1 in starved ghrelin-deficient mice caused a twofold increase in glucose production and raised blood glucose to levels seen in starved WT mice. Increased glucose production was accompanied by increases in plasma glycerol, fatty acids and ketone bodies, and hepatic triglycerides. All of these increases were abolished when the mice were treated with atglistatin, an inhibitor of adipose tissue triglyceride lipase. We conclude that IGF-1 stimulates adipose tissue lipolysis in starved mice and that this lipolysis supplies energy and substrates that restore hepatic gluconeogenesis. This action of IGF-1 in starved mice is in contrast to its known action in inhibiting adipose tissue lipase in fed mice. Surprisingly, the ghrelin-dependent maintenance of plasma IGF-1 in starved mice was not mediated by GH. Direct injection of GH into starved ghrelin-deficient mice failed to increase plasma IGF-1. These data call attention to an unsuspected role of IGF-1 in the adaptation to starvation.

Adipose tissue microenvironments during aging: Effects on stimulated lipolysis.

Adipose tissue is a critical organ for nutrient sensing, energy storage and maintaining metabolic health. The failure of adipose tissue homeostasis leads to metabolic disease that is seen during obesity or aging. Local metabolic processes are coordinated by interacting microenvironments that make up the complexity and heterogeneity of the adipose tissue. Catecholamine-induced lipolysis, a critical pathway in adipocytes that drives the release of stored triglyceride as free fatty acid after stimulation, is impaired during aging. The impairment of this pathway is associated with a failure to maintain a healthy body weight, core body-temperature during cold stress or mount an immune response. Along with impairments in aged adipocytes, aging is associated with an accumulation of inflammation, immune cell activation, and increased dysfunction in the nervous and lymphatic systems within the adipose tissue. Together these microenvironments support the initiation of stimulated lipolysis and the transport of free fatty acid under conditions of metabolic homeostasis. However, during aging, the defects in these cellular systems result in a reduction in ability to stimulate lipolysis. This review will focus on how the immune, nervous and lymphatic systems interact during tissue homeostasis, review areas that are impaired with aging and discuss areas of research that are currently unclear.

Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease.

BACKGROUND & AIMS: There is substantial inter-individual variability in the risk of non-alcoholic fatty liver disease (NAFLD). Part of which is explained by insulin resistance (IR) ('MetComp') and part by common modifiers of genetic risk ('GenComp'). We examined how IR on the one hand and genetic risk on the other contribute to the pathogenesis of NAFLD. METHODS: We studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D5-glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D2O (n = 61). RESULTS: We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the 'MetComp'. In contrast, the 'GenComp' was not accompanied by any substrate excess but was characterized by an increased hepatic mitochondrial redox state, as determined by serum ß-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum ß-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD. CONCLUSIONS: These data show that the mechanisms underlying 'Metabolic' and 'Genetic' components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD. LAY SUMMARY: The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates.

The Importance of Fatty Acids as Nutrients during Post-Exercise Recovery.

It is well recognized that whole-body fatty acid (FA) oxidation remains increased for several hours following aerobic endurance exercise, even despite carbohydrate intake. However, the mechanisms involved herein have hitherto not been subject to a thorough evaluation. In immediate and early recovery (0-4 h), plasma FA availability is high, which seems mainly to be a result of hormonal factors and increased adipose tissue blood flow. The increased circulating availability of adipose-derived FA, coupled with FA from lipoprotein lipase (LPL)-derived very-low density lipoprotein (VLDL)-triacylglycerol (TG) hydrolysis in skeletal muscle capillaries and hydrolysis of TG within the muscle together act as substrates for the increased mitochondrial FA oxidation post-exercise. Within the skeletal muscle cells, increased reliance on FA oxidation likely results from enhanced FA uptake into the mitochondria through the carnitine palmitoyltransferase (CPT) 1 reaction, and concomitant AMP-activated protein kinase (AMPK)-mediated pyruvate dehydrogenase (PDH) inhibition of glucose oxidation. Together this allows glucose taken up by the skeletal muscles to be directed towards the resynthesis of glycogen. Besides being oxidized, FAs also seem to be crucial signaling molecules for peroxisome proliferator-activated receptor (PPAR) signaling post-exercise, and thus for induction of the exercise-induced FA oxidative gene adaptation program in skeletal muscle following exercise. Collectively, a high FA turnover in recovery seems essential to regain whole-body substrate homeostasis.

Impact of skeletal muscle IL-6 on regulation of liver and adipose tissue metabolism during fasting.

The liver and adipose tissue are important tissues in whole-body metabolic regulation during fasting. Interleukin 6 (IL-6) is a cytokine shown to be secreted from contracting muscle in humans and suggested to signal to the liver and adipose tissue. Furthermore, skeletal muscle IL-6 has been proposed to play a role during fasting. Therefore the aim of the present study was to investigate the role of skeletal muscle IL-6 in the regulation of substrate production in the liver and adipose tissue during fasting. Male skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice and littermate floxed (control) mice fasted for 6 or 18 h (6 h fasting or 18 h fasting) with corresponding fed control groups (6 h fed or 18 h fed) and liver and adipose tissue were quickly obtained. Plasma ß-hydroxybutyrate increased and hepatic glucose, lactate and glycogen decreased with fasting. In addition, fasting increased phosphoenolpyruvate carboxykinase protein and phosphorylation of pyruvate dehydrogenase (PDH) in the liver as well as hormone-sensitive lipase (HSL)Ser660 and HSLSer563 phosphorylation, PDH phosphorylation, adipose triglyceride lipase phosphorylation and perilipin phosphorylation and protein content in adipose tissue without any effect of lack of skeletal muscle IL-6. In conclusion, fasting induced regulation of enzymes in adipose tissue lipolysis and glyceroneogenesis as well as regulation of hepatic gluconeogenic capacity and hepatic substrate utilization in mice. However, skeletal muscle IL-6 was not required for these fasting-induced effects, but had minor effects on markers of lipolysis and glyceroneogenesis in adipose tissue as well as markers of hepatic gluconeogenesis in the fed state.

Atglistatin ameliorates functional decline in heart failure via adipocyte-specific inhibition of adipose triglyceride lipase.

Despite advancements in therapies for cardiovascular disease and heart failure (HF), the incidence and prevalence of HF are increasing. Previous work has suggested that inhibiting adipose triglyceride lipase (ATGL) in adipose tissue during HF development may assist in the treatment of HF. The ability to specifically target the adipocyte as a potential treatment for HF is a novel approach that could significantly influence the management of HF in the future. Our objectives were to assess the cardiac structural and functional effects of pharmacological inhibition of ATGL in mice with HF, to assess whether ATGL inhibition works in an adipocyte-autonomous manner, and to determine the role that adiposity and glucose homeostasis play in this HF treatment approach. Using a known ATGL inhibitor, atglistatin, as well as mice with germline deletion of adipocyte-specific ATGL, we tested the effectiveness of ATGL inhibition in mice with pressure overload-induced HF. Here, we show that atglistatin can prevent the functional decline in HF and provide evidence that specifically targeting ATGL in the adipocyte is sufficient to prevent worsening of HF. We further demonstrate that the benefit resulting from atglistatin in HF is not dependent on previously suggested improvements in glucose homeostasis, nor are the benefits derived from increased adiposity. Overall, the results of this study suggest that adipocyte-specific pharmacological inhibition of ATGL may represent a novel therapeutic option for HF. NEW & NOTEWORTHY This work shows for the first time that the adipose triglyceride lipase (ATGL)-specific inhibitor atglistatin can prevent worsening heart failure. Furthermore, using mice with adipocyte-specific ATGL ablation, this study demonstrates that ATGL inhibition works in an adipocyte-autonomous manner to ameliorate a functional decline in heart failure. Overall, this work demonstrates that specifically targeting the adipocyte to inhibit ATGL is a potential treatment for heart failure.

Maternal adipose tissue becomes a source of fatty acids for the fetus in fasted pregnant rats given diets with different fatty acid compositions.

PURPOSE: The utilization of long-chain polyunsaturated fatty acids (LCPUFA) by the fetus may exceed its capacity to synthesize them from essential fatty acids, so they have to come from the mother. Since adipose tissue lipolytic activity is greatly accelerated under fasting conditions during late pregnancy, the aim was to determine how 24 h fasting in late pregnant rats given diets with different fatty acid compositions affects maternal and fetal tissue fatty acid profiles. METHODS: Pregnant Sprague-Dawley rats were given isoenergetic diets containing 10% palm-, sunflower-, olive- or fish-oil. Half the rats were fasted from day 19 of pregnancy and all were studied on day 20. Triacylglycerols (TAG), glycerol and non-esterified fatty acids (NEFA) were analyzed by enzymatic methods and fatty acid profiles were analyzed by gas chromatography. RESULTS: Fasting caused increments in maternal plasma NEFA, glycerol and TAG, indicating increased adipose tissue lipolytic activity. Maternal adipose fatty acid profiles paralleled the respective diets and, with the exception of animals on the olive oil diet, maternal fasting increased the plasma concentration of most fatty acids. This maintains the availability of LCPUFA to the fetus during brain development. CONCLUSIONS: The results show the major role played by maternal adipose tissue in the storage of dietary fatty acids during pregnancy, thus ensuring adequate availability of LCPUFA to the fetus during late pregnancy, even when food supply is restricted.

Flaxseed Oil Alleviates Chronic HFD-Induced Insulin Resistance through Remodeling Lipid Homeostasis in Obese Adipose Tissue.

Emerging evidence suggests that higher circulating long-chain n-3 polyunsaturated fatty acids (n-3PUFA) levels were intimately associated with lower prevalence of obesity and insulin resistance. However, the understanding of bioactivity and potential mechanism of α-linolenic acid-rich flaxseed oil (ALA-FO) against insulin resistance was still limited. This study evaluated the effect of FO on high-fat diet (HFD)-induced insulin resistance in C57BL/6J mice focused on adipose tissue lipolysis. Mice after HFD feeding for 16 weeks (60% fat-derived calories) exhibited systemic insulin resistance, which was greatly attenuated by medium dose of FO (M-FO), paralleling with differential accumulation of ALA and its n-3 derivatives across serum lipid fractions. Moreover, M-FO was sufficient to effectively block the metabolic activation of adipose tissue macrophages (ATMs), thereby improving adipose tissue insulin signaling. Importantly, suppression of hypoxia-inducible factors HIF-1α and HIF-2α were involved in FO-mediated modulation of adipose tissue lipolysis, accompanied by specific reconstitution of n-3PUFA within adipose tissue lipid fractions.