Jensen, Michael D.

Hyperglycemia in prediabetes is accompanied by increased amino acid (AA) concentrations and impaired suppression of glucagon secretion by glucose. It is unknown whether an abnormal response to AA contributes or hepatic steatosis exacerbates α-cell dysfunction. Therefore, lean participants and participants with obesity (with and without hepatic steatosis) were studied on two occasions in random order using a graded glucose infusion. Saline or an AA mixture was infused. The glucagon secretion rate (GSR) was derived from peripheral glucagon concentrations, and the change in glucose required to reduce GSR by 50% (G50) was calculated for each participant. AAs were measured during the experiment. On both occasions, experimental conditions produced a progressive rise in insulin secretion and an inverse exponential suppression of glucagon. G50 did not differ between groups in response to glucose alone. AA infusion did not change G50 in lean participants. G50 increased during AA infusion in participants with obesity with and without hepatic steatosis, leading us to report these participants as a single group. The relative change in AA concentrations across study days was generally similar between groups. We conclude that despite a normal response to glucose, obesity increases α-cell responses to AA in humans. Article Highlights The aim of this study was to understand the pathogenesis of α-cell dysfunction in prediabetes. The primary hypothesis was that α-cell responsivity to glucose (reduction of the glucagon secretion rate by 50%) is impaired by amino acid (AA) infusion. A secondary hypothesis was that this abnormal response is exacerbated by hepatic steatosis. AA infusion impaired α-cell suppression in response to rising glucose in participants with obesity, but not in lean participants, despite a normal response to glucose alone. This abnormal response was unaffected by the presence or absence of hepatic steatosis. It seems likely that an abnormal α-cell response to AAs precedes an abnormal response to glucose alone.

Adipose tissue (AT) lipolysis insulin resistance results in excess free fatty acid (FFA) release. We tested the hypothesis that the ability of insulin to suppress AT lipolysis is unrelated to the ability of niacin to suppress lipolysis, because niacin acts through a different proximal signaling pathway. Ten volunteers (5 women and 5 men) with upper-body obesity and/or type 2 diabetes mellitus (T2DM) underwent two study visits with overnight intravenous infusions of niacin (1.4 mg/min) or saline, followed by a hyperinsulinemic-euglycemic clamp. FFA-palmitate Ra was measured using [U-13C] and [2H9]palmitate infusions; abdominal AT biopsies were performed before and during the insulin clamp. The suppression of FFA-palmitate Ra by insulin on the saline control day and by niacin after an overnight infusion were highly correlated (r = −0.93, P < 0.001). Fasting AT Akt (pAktS473/474-to-panAkt ratio, P = 0.01) and perilipin 1 (PLN1) (pPLN1S552-to-panPLN1 ratio, P = 0.02) phosphorylation were less during niacin treatment than in the saline control study. Because the suppression of lipolysis by insulin and niacin are highly correlated within individuals and because niacin and insulin act through different proximal signaling pathways, we propose dysregulated AT lipolysis in obesity/T2DM is due to dysfunction(s) in distal lipolysis proteins rather than isolated “insulin resistance.” Article Highlights We undertook this study to compare adipose tissue lipolysis responses to insulin and niacin in humans. We tested the hypothesis that adipose tissue insulin resistance would be unrelated to adipose tissue niacin resistance. The suppression of lipolysis by insulin and niacin were highly correlated. Dysregulated adipose tissue lipolysis in obesity/type 2 diabetes is due to dysfunction(s) in distal lipolysis proteins rather than isolated “insulin resistance.”

Background: Whether there are sex and obesity differences in fat oxidation and free fatty acid (FFA) mobilization during low-intensity exercise is unclear. Methods: We studied 21 (nine females) participants without and 24 (16 females) with obesity during 5 h of treadmill walking (~2 mph). We measured energy expenditure (EE) and substrate oxidation (indirect calorimetry) and FFA-palmitate kinetics and oxidation with isotopic palmitate infusions ([U- 13 C]palmitate and [1- 14 C]palmitate or [9,10- 3 H]palmitate). Skeletal muscle samples were collected at 1.5 and 5 h of exercise and 24 h after exercise. We calculated fatty acid (FA) oxidation, palmitate rate of disappearance (Rd), and intramyocellular triglyceride-derived palmitate fractions during exercise. Results: At rest, EE was 1.24 ± 0.23 kcal/min, with FA oxidation contributing 49 ± 13% of total EE. During exercise, FA oxidation accounted for 73 ± 8% of EE, and was not different between males and females ( P = 0.34). Plasma FFA-palmitate concentrations were greater in females than males ( P = 0.003), mean palmitate Rd and plasma palmitate clearance were not different ( P = 0.32 and 0.14, respectively). Plasma FFA-palmitate Rd was correlated with EE ( r = 0.49, P = 0.001), with a proportionally greater Rd response in females ( P < 0.001). Although absolute plasma FFA-palmitate oxidation rates were comparable between sexes, the percent contribution of FFA-palmitate oxidation to EE was greater in females ( P = 0.001). During exercise, intramyocellular triglyceride-palmitate fraction amounts remained stable. Conclusions: Lipid oxidation during low-intensity exercise is similar in males and females, independent of obesity, although next-day values were greater in participants with normal weight. EE correlates with plasma palmitate disappearance rates, but is proportionally greater in females. The contribution of plasma palmitate oxidation is greater in females than in males during low-intensity exercise.

Greater degrees of aerobic fitness are associated with greater insulin-mediated muscle glucose uptake. Insulin regulates adipose tissue lipolysis, whether aerobic fitness affects insulin’s ability to regulate lipolysis is unknown. We found that greater fitness is associated with improved adipose tissue insulin responsiveness independent of age, sex, BMI, visceral adipose tissue, body fat (kg), percent body fat, and adipocyte size. This suggests that exercise, if it improves fitness, may improve both adipose tissue and muscle function.

Tryptophan hydroxylase (TPH) is a rate-limiting enzyme for serotonin or 5-hydroxytryptamine (5-HT) synthesis. Previously, adipocyte TPH1 has been linked to increased adipose 5-HT, reduced brown adipose tissue (BAT) thermogenesis, and obesity. However, the role of TPH2, a neural isoform highly expressed in obese adipose tissue, is unknown. Here, we report that adipose tissue expression of TPH2 is dramatically elevated in mice with diet-induced obesity (DIO) and ob/ob mice, as well as in obese humans. In mice fed a high-fat diet, adipocyte TPH2 deficiency improved DIO-induced metabolic complications, enhanced BAT thermogenesis, and increased intestinal energy-harvesting efficiency without affecting adiposity. Conversely, TPH2 overexpression in epididymal adipocytes of chow-fed mice raised adipose and plasma 5-HT levels, suppressed BAT thermogenesis, and exacerbated obesity and metabolic dysfunction. We found that obesity-induced hyperinsulinemia upregulated adipocyte TPH2 expression via activation of mechanistic target of rapamycin complex 1 and SREBP1. In humans, TPH2 mRNA levels in subcutaneous adipose tissue, but not those of TPH1 , are positively correlated with fasting plasma insulin concentrations. In summary, our study demonstrates that obesity-associated increases in adipocyte TPH2 can regulate distal tissue physiology and energy metabolism, suggesting that TPH2 could be a potential therapeutic target for obesity and its associated complications.

Accurate measures of insulin regulation of adipose tissue lipolysis (free fatty acid release rates) in humans can be accomplished using a two-step, hyperinsulinemic clamp experimental design, but careful scrutiny of the data is needed. The FFA palmitate IC 50 measure is reproducible in weight-stable adults and responds to treatment interventions in a quantitative manner.