Neutralization of tumor necrosis factor-alpha reverses insulin resistance in skeletal muscle but not adipose tissue

We examined the possible role of tumor necrosis factor-alpha (TNF-alpha) as a mediator of insulin resistance in maturing male Sprague-Dawley rats. Rats were treated either with goat anti-murine TNF-alpha IgG (anti-TNF-alpha) or goat nonimmune IgG (NI) for 7 days. Vascular catheters were implanted, and rats were fasted overnight before hyperinsulinemic euglycemic clamp (HUC) studies were performed. TNF-alpha neutralization increased the rate of glucose infusion required to maintain euglycemia by 68%. Insulin-stimulated glucose transport into individual tissues was measured after bolus administration of 2-deoxy-[(14)C]glucose during HUC. Anti-TNF-alpha administration increased glucose transport in muscles composed predominantly of fast-twitch fibers: white gastrocnemius muscle (68% increase) and tibialis anterior muscle (64% increase). There were nonsignificant trends for increased glucose transport in the slow-twitch soleus muscle and in the mixed-fiber red gastrocnemius muscle. Glucose transport was unchanged in visceral and subcutaneous fat. Anti-TNF treatment did not alter body weight, muscle mass, or fat mass. Anti-TNF-alpha did not alter the distribution of the 17-kDa and 26-kDa forms of TNF-alpha in either muscle or fat. However, anti-TNF-alpha treatment caused an approximately 50% reduction in the secretion of TNF-alpha bioactivity in vitro by explants of visceral and subcutaneous fat. We conclude that TNF-alpha neutralization reversed insulin resistance substantially in fast-twitch muscle and may have done so in other muscles, while having little effect in fat. TNF-alpha neutralization was accompanied by reduced TNF-alpha bioactivity without tissue depletion of TNF-alpha protein.Journal ArticleFinal article publishe

A–B. Serum total adiponectin concentrations and adipose tissue adiponectin expression in young male rats receiving sham surgery (SHAM), gonadectomy (GX), GX plus supraphysiologic testosterone-enanthate (GX+TE), or GX plus graded doses of trenbolone enanthate (GX+Low TREN, GX+Mod TREN, and GX+High TREN).

<p>Values are Means±SE, n = 8–10/group (serum) and n = 6–10/group (adipose tissue). Letters a–e indicate differences from respectively labeled groups at p<0.05 or * p<0.01 (a = vs. SHAM, b = vs. GX, c = vs. GX+TE, d = vs. GX+Low TREN, e = vs. GX+Mod TREN, f = vs. GX+High TREN). A representative Western blot image is included as <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047315#pone.0047315.s001" target="_blank">Figure S1A</a>.</p

A–F. Associations between serum total adiponectin and the serum sex-hormone measurements for young male and female rats that received Sham surgery (SHAM), gonadectomy (GX), or GX plus supraphysiologic testosterone-enanthate (TE).

<p>GX involved an orchiectomy (males) or an ovariectomy (females). Values represent individual animals, n = 24–27 for individual analyses and n = 51–55 for combined analysis.</p

Associations between serum total adiponectin and trenbolone for young male rats that received gonadectomy (GX) or GX plus graded doses of trenbolone-enanthate (GX+Low TREN, GX+Mod TREN, and GX+High TREN).

<p>Values represent individual animals, n = 8–9/group.</p

Associations between serum total adiponectin and visceral fat mass for young male rats that received sham surgery (SHAM), gonadectomy (GX), GX plus supraphysiologic testosterone-enanthate (GX+TE), or GX plus graded doses of trenbolone-enanthate (GX+Low TREN, GX+Mod TREN, and GX+High TREN).

<p>Values represent individual animals, n = 8–10/group.</p

A–B. Serum total adiponectin concentrations in young male and female rats receiving sham surgery (SHAM), gonadectomy (GX), or GX plus supraphysiological testosterone-enanthate (TE).

<p>GX involved an orchiectomy (males) or an ovariectomy (females). Values are Means±SE, n = 8–10/group. Letters a–f indicated differences from respectively labeled groups at p<0.05 or * p<0.01 (MALES: a = vs. SHAM, b = vs. GX, c = vs. GX+TE; FEMALES: d = vs. SHAM, e = vs. GX, f = vs. GX+TE).</p

Serum high-molecular weight (HMW) adiponectin concentrations and HMW as a percent of total adiponectin in young male rats receiving sham surgery (SHAM), gonadectomy (GX), GX plus supraphysiologic testosterone-enanthate (GX+TE), or GX plus graded doses of trenbolone enanthate (GX+Low TREN, GX+Mod TREN, and GX+High TREN).

<p>Serum high-molecular weight (HMW) adiponectin concentrations and HMW as a percent of total adiponectin in young male rats receiving sham surgery (SHAM), gonadectomy (GX), GX plus supraphysiologic testosterone-enanthate (GX+TE), or GX plus graded doses of trenbolone enanthate (GX+Low TREN, GX+Mod TREN, and GX+High TREN).</p