The absence of GH signaling affects the susceptibility to high-fat diet-induced hypothalamic inflammation in male mice

TY - JOUR

T1 - The absence of GH signaling affects the susceptibility to high-fat diet-induced hypothalamic inflammation in male mice

AU - Baquedano, Eva

AU - Ruiz-Lopez, Ana M

AU - Sustarsic, Elahu G

AU - Herpy, James

AU - List, Edward O.

AU - Chowen, Julie A

AU - Frago, Laura M

AU - Kopchick, John J.

AU - Argente, Jesús

PY - 2014/12/1

Y1 - 2014/12/1

N2 - GH is important in metabolic control, and mice with disruption of the gene encoding the GH receptor (GHR) and GH binding protein (GHR-/- mice) are dwarf with low serum IGF-1 and insulin levels, high GH levels, and increased longevity, despite their obesity and altered lipid and metabolic profiles. Secondary complications of high-fat diet (HFD)-induced obesity are reported to be associated with hypothalamic inflammation and gliosis. Because GH and IGF-1 can modulate inflammatory processes, our objective was to evaluate the effect of HFD on hypothalamic inflammation/gliosis in the absence of GH signaling and determine how this correlates with changes in systemic metabolism. On normal chow, GHR-/- mice had a higher percentage of fat mass and increased circulating nonesterified free fatty acids levels compared with wild type (WT), and this was associated with increased hypothalamic TNF-α and phospho-JNK levels. After 7 weeks on a HFD, both WT and GHR-/- mice had increased weight gain, with GHR-/- mice having a greater rise in their percentage of body fat. In WT mice, HFD-induced weight gain was associated with increased hypothalamic levels of phospho-JNK and the microglial marker Iba-1 (ionized calcium-binding adapter molecule 1) but decreased cytokine production. Moreover, in GHR-/- mice, the HFD decreased hypothalamic inflammatory markers to WT levels with no indication of gliosis. Thus, the GH/IGF-1 axis is important in determining not only adipose tissue accrual but also the inflammatory response to HFD. However, how hypothalamic inflammation/gliosis is defined will determine whether it can be considered a common feature of HFD-induced obesity.

AB - GH is important in metabolic control, and mice with disruption of the gene encoding the GH receptor (GHR) and GH binding protein (GHR-/- mice) are dwarf with low serum IGF-1 and insulin levels, high GH levels, and increased longevity, despite their obesity and altered lipid and metabolic profiles. Secondary complications of high-fat diet (HFD)-induced obesity are reported to be associated with hypothalamic inflammation and gliosis. Because GH and IGF-1 can modulate inflammatory processes, our objective was to evaluate the effect of HFD on hypothalamic inflammation/gliosis in the absence of GH signaling and determine how this correlates with changes in systemic metabolism. On normal chow, GHR-/- mice had a higher percentage of fat mass and increased circulating nonesterified free fatty acids levels compared with wild type (WT), and this was associated with increased hypothalamic TNF-α and phospho-JNK levels. After 7 weeks on a HFD, both WT and GHR-/- mice had increased weight gain, with GHR-/- mice having a greater rise in their percentage of body fat. In WT mice, HFD-induced weight gain was associated with increased hypothalamic levels of phospho-JNK and the microglial marker Iba-1 (ionized calcium-binding adapter molecule 1) but decreased cytokine production. Moreover, in GHR-/- mice, the HFD decreased hypothalamic inflammatory markers to WT levels with no indication of gliosis. Thus, the GH/IGF-1 axis is important in determining not only adipose tissue accrual but also the inflammatory response to HFD. However, how hypothalamic inflammation/gliosis is defined will determine whether it can be considered a common feature of HFD-induced obesity.

KW - Animals

KW - Blood Glucose

KW - Body Composition

KW - Body Size

KW - Cytokines

KW - Diet, High-Fat

KW - Gliosis

KW - Growth Hormone

KW - Hypothalamic Diseases

KW - Hypothalamus

KW - Inflammation

KW - Insulin

KW - Insulin-Like Growth Factor I

KW - Lipids

KW - Male

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Neuropeptides

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1210/en.2014-1367

DO - 10.1210/en.2014-1367

M3 - Journal article

C2 - 25237935

SN - 0013-7227

VL - 155

SP - 4856

EP - 4867

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 12

ER -