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Objective: The aim of this study was to evaluate the browning and origin of fatty acids (FAs) in the maintenance of triacylglycerol (TG) storage and/or as fuel for thermogenesis in perirenal adipose tissue (periWAT) and inguinal adipose tissue (ingWAT) of rats fed a low-protein, high-carbohydrate (LPHC) diet., Methods: LPHC (6% protein, 74% carbohydrate) or control (C; 17% protein, 63% carbohydrate) diets were administered to rats for 15 d. The tissues were stained with hematoxylin and eosin for histologic analysis. The content of uncoupling protein 1 (UCP1) was determined by immunofluorescence. Levels of T-box transcription factor (TBX1), PR domain containing 16 (PRDM16), adipose triacylglycerol lipase (ATGL), hormone-sensitive lipase, lipoprotein lipase (LPL), glycerokinase, phosphoenolpyruvate carboxykinase (PEPCK), glucose transporter 4, β 3 -adrenergic receptor (AR), β 1 -AR, protein kinase A (PKA), adenosine-monophosphate-activated protein kinase (AMPK), and phospho-AMPK were determined by immunoblotting. Serum fibroblast growth factor 21 (FGF21) was measured using a commercial kit (Student's t tests, P < 0.05)., Results: The LPHC diet increased FGF21 levels by 150-fold. The presence of multilocular adipocytes, combined with the increased contents of UCP1, TBX1, and PRDM16 in periWAT of LPHC-fed rats, suggested the occurrence of browning. The contents of β 1 -AR and LPL were increased in the periWAT. The ingWAT showed higher ATGL and PEPCK levels, phospho-AMPK/AMPK ratio, and reduced β 3 -AR and PKA levels., Conclusion: These findings suggest that browning occurred only in the periWAT and that higher utilization of FAs from blood lipoproteins acted as fuel for thermogenesis. Increased glycerol 3-phosphate generation by glyceroneogenesis increased FAs reesterification from lipolysis, explaining the increased TG storage in the ingWAT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The our objective was to investigate the adaptations induced by a low-protein, high-carbohydrate (LPHC) diet in growing rats, which by comparison with the rats fed a control (C) diet at displayed lower fasting glycemia and similar fasting insulinemia, despite impairment in insulin signaling in adipose tissues. In the insulin tolerance test the LPHC rats showed higher rates of glucose disappearance (30%) and higher tolerance to overload of glucose than C rats. The glucose uptake by the soleus muscle, evaluated in vivo by administration of 2-deoxy-[(14)C]glucose, increased by 81%. The phosphoenolpyruvate carboxykinase content and the incorporation of [1-(14)C]pyruvate into glucose was also higher in the slices of liver from the LPHC rats than in those from C rats. The LPHC rats showed increases in l-lactate as well as in other gluconeogenic precursors in the blood. These rats also had a higher hepatic production of glucose, evaluated by in situ perfusion. The data obtained indicate that the main substrates for gluconeogenesis in the LPHC rats are l-lactate and glycerol. Thus, we concluded that the fasting glycemia in the LPHC animals was maintained mainly by increases in the hepatic gluconeogenesis from glycerol and l-lactate, compensating, at least in part, for the higher glucose uptake by the tissues.

The aim of this study was to investigate tumor necrosis factor alpha (TNF-α)- and noradrenaline (NE)-stimulated lipolysis in retroperitoneal (RWAT) and epididymal (EAT) white adipose tissue as a means of understanding how low-protein, high-carbohydrate (LPHC) diet-fed rats maintain their lipid storage in a catabolic environment (marked by increases in serum TNF-α and corticosterone and sympathetic flux to RWAT and EAT), as previously observed. Adipocytes or tissues from the RWAT and EAT of rats fed an LPHC diet and rats fed a control (C) diet for 15 days were used in the experiments. The adipocytes from both tissues of the LPHC rats exhibited lower TNF-α- stimulated lipolysis compared to adipocytes from the C rats. The intracellular lipolytic agents IBMX, DBcAMPc and FSK increased lipolysis in both tissues from rats fed the C and LPHC diets compared to basal lipolysis; however, the effect was approximately 2.5-fold lower in adipocytes from LPHC rats. The LPHC diet induced a marked reduction in the β3 and α2-AR, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) content in RWAT and EAT. The LPHC diet did not affect TNF-α receptor 1 content but did induce a reduction in ERK p44/42 in both tissues. The present work indicates that RWAT and EAT from LPHC rats have an impairment in the lipolysis signaling pathway activated by NE and TNF-α, and this impairment explains the reduced response to these lipolytic stimuli, which may be fundamental to the maintenance of lipid storage in LPHC rats.

We had previously shown that adipose tissue increased in rats fed a low-protein, high-carbohydrate (LPHC) diet (6% protein, 74% carbohydrate) without a simultaneous increase in the de novo fatty acids (FA) synthesis. In addition, impairment in insulin signaling in adipose tissues was observed in these rats. For this study, we hypothesized that the insulin signaling pathway is preserved in the livers from these rats, which contributes to an increase in liver lipogenesis and, consequently, an increase in the weight of the adipose tissue. We also hypothesized that glycerol from triacylglycerol is an important substrate for FA synthesis. Our results showed that administration of the LPHC diet induced an increase in the in vivo rate of total FA synthesis (150%) as well as FA synthesis from glucose (270%) in the liver. There were also increased rates of [U-¹⁴C]glycerol incorporation into glyceride-FA (15-fold), accompanied by increased glycerokinase content (30%) compared with livers of rats fed the control diet. The LPHC diet did not change the glycerol-3-phosphate generation from either glucose or glyceroneogenesis. There was an increase in the insulin sensitivity in liver from LPHC-fed rats, as evidenced by increases in IR(β) (35%) levels and serine/threonine protein kinase (AKT) levels (75%), and basal (95%) and insulin-stimulated AKT phosphorylation (105%) levels. The LPHC diet also induced an increase in the liver sterol regulatory element-binding protein-1c content (50%). In summary, these data confirmed the hypothesis that lipogenesis and insulin signaling are increased in the livers of LPHC-fed rats and that glycerol is important not only for FA esterification but also for FA synthesis., (Published by Elsevier Inc.)

A low-protein, high-carbohydrate (LPHC) diet for 15 days increased the lipid content in the carcass and adipose tissues of rats. The aim of this work was to investigate the mechanisms of this lipid increase in the retroperitoneal white adipose tissue (RWAT) of these animals. The LPHC diet induced an approximately two- and tenfold increase in serum corticosterone and TNF-α, respectively. The rate of de novo fatty acid (FA) synthesis in vivo was reduced (50%) in LPHC rats, and the lipoprotein lipase activity increased (100%). In addition, glycerokinase activity increased (60%), and the phosphoenolpyruvate carboxykinase content decreased (27%). Basal [U-¹⁴C]-glucose incorporation into glycerol-triacylglycerol did not differ between the groups; however, in the presence of insulin, [U-¹⁴C]-glucose incorporation increased by 124% in adipocytes from only control rats. The reductions in IRS1 and AKT content as well as AKT phosphorylation in the RWAT from LPHC rats and the absence of an insulin response suggest that these adipocytes have reduced insulin sensitivity. The increase in NE turnover by 45% and the lack of a lipolytic response to NE in adipocytes from LPHC rats imply catecholamine resistance. The data reveal that the increase in fat storage in the RWAT of LPHC rats results from an increase in FA uptake from circulating lipoproteins and glycerol phosphorylation, which is accompanied by an impaired lipolysis that is activated by NE.