Protease inhibitors (PIs) are widely assumed to be associated with a syndrome of insulin resistance accompanied by hyperlipidemia and fat redistribution. Insulin resistance in HIV infection has numerous other causes, however, which include not only the direct effects of antiretroviral drugs but also factors such as aging and restoration to health accompanied by fat accumulation. Studies of PIs in HIV-infected and noninfected patients indicate that some of these drugs are associated with reduced insulin sensitivity (greater acute versus chronic effects) that may be due to direct blockade of the insulin-sensitive glucose transporter in muscle and fat cells. Other studies have shown that insulin levels increase over time with antiretroviral therapy, likely the result of improved health, fat accumulation, and aging, and that increases in visceral fat and upper trunk fat are associated with a higher risk of insulin resistance in HIV-infected and -uninfected individuals alike. This article summarizes a presentation on insulin resistance in HIV infection made by Carl Grunfeld, MD, PhD, at the 10th Annual Ryan White HIV/AIDS Program Clinical Update in Phoenix in June 2007.

Inflammation produces marked changes in lipid metabolism, including increased serum fatty acids (FAs) and triglycerides (TGs), increased hepatic TG production and VLDL secretion, increased adipose tissue lipolysis, and decreased FA oxidation in liver and heart. Lipopolysaccharide (LPS) also increases TG and cholesteryl ester levels in kidneys. Here we confirm these findings and define potential mechanisms. LPS decreases renal FA oxidation by 40% and the expression of key proteins required for oxidation of FAs, including FA transport protein-2, fatty acyl-CoA synthase, carnitine palmitoyltransferase-1, medium-chain acyl-CoA dehydrogenase, and acyl-CoA oxidase. Similar decreases were observed in peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice. LPS also caused a reduction in renal mRNA levels of PPARalpha (75% decrease), thyroid hormone receptor alpha (TRalpha) (92% decrease), and TRbeta (84% decrease), whereas PPARbeta/delta and gamma were not altered. Expression of PGC1 alpha and beta, coactivators required for PPARs and TR, was also decreased in kidneys of LPS-treated mice, as were mitochondrial genes regulated by PGC1 (Atp5g1, COX5a, Idh3a, and Ndufs8). Decreased renal FA oxidation could be a by-product of the systemic coordinated host response to increase FAs and TGs available for host defense and/or tissue repair. However, the kidney requires energy to support its transport functions, and the inability to generate energy via FA oxidation might contribute to the renal failure seen in severe sepsis.

Inflammation induces marked changes in lipid and lipoprotein metabolism. Proprotein convertase subtilisin kexin 9 (PCSK9) plays an important role in regulating LDL receptor degradation. Here, we demonstrate that LPS decreases hepatic LDL receptor protein but at the same time hepatic LDL receptor mRNA levels are not decreased. We therefore explored the effect of LPS on PCSK9 expression. LPS results in a marked increase in hepatic PCSK9 mRNA levels (4h 2.5-fold increase; 38h 12.5-fold increase). The increase in PCSK9 is a sensitive response with 1microg LPS inducing a (1/2) maximal response. LPS also increased PCSK9 expression in the kidney. Finally, zymosan and turpentine, other treatments that induce inflammation, also stimulated hepatic expression of PCSK9. Thus, inflammation stimulates PCSK9 expression leading to increased LDL receptor degradation and decreasing LDL receptors thereby increasing serum LDL, which could have beneficial effects on host defense.

Infection and inflammation affect adipose triglyceride metabolism, resulting in increased plasma free fatty acid (FFA) and VLDL levels during the acute-phase response. Lipin-1, a multifunctional protein, plays a critical role in adipose differentiation, mitochondrial oxidation, and triglyceride synthesis. Here, we examined whether LPS [a Toll-like receptor (TLR)-4 activator], zymosan (a TLR-2 activator), and proinflammatory cytokines regulate lipin-1 in adipose tissue. LPS administration caused a marked decrease in the levels of lipin-1 mRNA and protein in adipose tissue. The decrease in lipin-1 mRNA levels occurred rapidly and lasted for at least 24 h. In contrast, lipin-2 and -3 mRNA levels did not change, suggesting specific repression of lipin-1. Zymosan similarly decreased lipin-1 mRNA without affecting lipin-2 or lipin-3 mRNA levels. To determine the pathways by which LPS repressed lipin-1, we examined the effect of proinflammatory cytokines on cultured adipocytes. In 3T3-L1 adipocytes, TNF-alpha, IL-1beta, and IFN-gamma, but not LPS or IL-6, caused a decrease in lipin-1 mRNA levels. Furthermore, TNF-alpha and IL-1beta administration also decreased mRNA levels of lipin-1 in adipose tissue in mice. Importantly, the LPS-induced decrease in lipin-1 mRNA levels was significantly but not totally blunted in TNF-alpha/IL-1 receptor-null mice compared with controls, suggesting key roles for TNF-alpha/IL-1beta and other cytokines in mediating LPS-induced repression of lipin-1. Together, our results demonstrate that expression of lipin-1, one of the essential triglyceride synthetic enzymes, was suppressed by LPS, zymosan, and proinflammatory cytokines in mouse adipose tissue and in cultured 3T3-L1 adipocytes, which could contribute to a decrease in the utilization of FFA to synthesize triglycerides in adipose tissue, thus promoting the release of FFA into the circulation.

OBJECTIVE

To assess by race/ethnicity long-term changes in metabolic parameters and body composition among treatment-naive persons initiating antiretroviral therapy (ART).

METHODS

We compared changes in 398 participants (African American n = 243, Latino n = 43, white n = 112) initiating ART. At baseline, 1-month (metabolic parameters only) and 4-month follow-up intervals (anthropometric measurements) were performed and fasting metabolic parameters measured. Rates of change over time and overall mean changes from baseline were compared.

RESULTS

Latinos had the greatest increase in glucose and insulin resistance and greatest loss of mid-arm and mid-thigh subcutaneous tissue areas. On average, mid-arm and mid-thigh nonsubcutaneous tissue areas increased in all races. Waist subcutaneous tissue area decreased only for Latinos. Visceral tissue area increased the most for Latinos and whites. For all groups, the initial increase in high-density lipoprotein cholesterol was sustained. The initial increase in low-density lipoprotein cholesterol was followed by a gradual decline in all groups. Triglycerides increased for all groups; the increase being the least for African Americans.

CONCLUSIONS

In this prospective long-term evaluation, changes in metabolic parameters and body composition varied across race groups. Latinos experienced the most unfavorable changes. Such changes should be monitored over time as the identified differences may impact ART selection.

CONTEXT

Leptin deficiency is associated with dyslipidemia and insulin resistance in animals and humans with lipoatrophy; leptin replacement ameliorates these abnormalities.

OBJECTIVE

The objective of the study was to evaluate the effects of leptin therapy in lipoatrophic HIV-infected patients with dyslipidemia and hypoleptinemia.

DESIGN

This was a 6-month, open-label, proof-of-principle pilot study.

SETTING

Metabolic ward studies were performed before and 3 and 6 months after leptin treatment.

PARTICIPANTS

Participants included eight HIV-infected men with lipoatrophy, fasting triglycerides greater than 300 mg/dl, and serum leptin less than 3 ng/ml.

INTERVENTION

Recombinant human leptin was given by sc injection (0.01 mg/kg and 0.03 mg/kg twice daily for successive 3 month periods).

OUTCOME MEASURES

Measures included fat distribution by magnetic resonance imaging and dual-energy X-ray absorptiometry; fasting lipids; insulin sensitivity by euglycemic hyperinsulinemic clamp; endogenous glucose production, gluconeogenesis, glycogenolysis, and whole-body lipolysis by stable isotope tracer studies; oral glucose tolerance testing; liver fat by proton magnetic resonance spectroscopy; and safety.

RESULTS

Visceral fat decreased by 32% (P = 0.001) with no changes in peripheral fat. There were significant decreases in fasting total (15%, P = 0.012), direct low-density lipoprotein (20%, P = 0.002), and non-high-density lipoprotein (19%, P = 0.005) cholesterol. High-density lipoprotein cholesterol increased. Triglycerides, whole-body lipolysis, and free fatty acids decreased during fasting and hyperinsulinemia. Fasting insulin decreased. Endogenous glucose production decreased during fasting and hyperinsulinemia, providing evidence of improved hepatic insulin sensitivity. Leptin was well tolerated but decreased lean mass.

CONCLUSIONS

Leptin treatment was associated with marked improvement in dyslipidemia. Hepatic insulin sensitivity improved and lipolysis decreased. Visceral fat decreased with no exacerbation of peripheral lipoatrophy. Results from this pilot study suggest that leptin warrants further study in patients with HIV-associated lipoatrophy.