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. 2011 Feb 2;13(2):183-94.
doi: 10.1016/j.cmet.2011.01.008.

Brain insulin controls adipose tissue lipolysis and lipogenesis

Thomas Scherer  1 , James O'Hare, Kelly Diggs-Andrews, Martina Schweiger, Bob Cheng, Claudia Lindtner, Elizabeth Zielinski, Prashant Vempati, Kai Su, Shveta Dighe, Thomas Milsom, Michelle Puchowicz, Ludger Scheja, Rudolf Zechner, Simon J Fisher, Stephen F Previs, Christoph Buettner
Affiliations

Brain insulin controls adipose tissue lipolysis and lipogenesis

Thomas Scherer et al. Cell Metab. .

Abstract

White adipose tissue (WAT) dysfunction plays a key role in the pathogenesis of type 2 diabetes (DM2). Unrestrained WAT lipolysis results in increased fatty acid release, leading to insulin resistance and lipotoxicity, while impaired de novo lipogenesis in WAT decreases the synthesis of insulin-sensitizing fatty acid species like palmitoleate. Here, we show that insulin infused into the mediobasal hypothalamus (MBH) of Sprague-Dawley rats increases WAT lipogenic protein expression, inactivates hormone-sensitive lipase (Hsl), and suppresses lipolysis. Conversely, mice that lack the neuronal insulin receptor exhibit unrestrained lipolysis and decreased de novo lipogenesis in WAT. Thus, brain and, in particular, hypothalamic insulin action play a pivotal role in WAT functionality.

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Conflict of interest statement

The authors declare that no competing financial interest exists.

Figures

Figure 1
Figure 1. Brain insulin suppresses whole body lipolysis
(A) Experimental protocol of the euglycemic clamp studies of SD rats. ICV or MBH insulin infusions were performed during basal insulin clamps (1 mU · kg−1 · min−1) and compared to rats subjected to hyperinsulinemic clamps (3 mU · kg−1 · min−1), while glycerol and glucose fluxes were determined through tracer dilution techniques. (B, C) Ra glycerol during basal (B) and clamped (C) conditions (n ≥ 3 per group). (D) Change of plasma NEFA levels compared to baseline during the 6 hr infusion protocol. Arrowhead marks the start of the clamp at time point 120 min (n ≥ 4 per group). (E) AUC of Fig. 1D comparing vehicle to ICV and MBH insulin infused rats prior to the start of the clamp study (time point -120 to 120 min, n ≥ 4 per group). (F) Plasma insulin levels during baseline (time point −120 to 120 min pre-clamp period) and the clamp (120 to 240 min, n ≥ 6 per group). (G, H, I) Plasma glucagon, leptin and adiponectin levels of MBH vehicle and insulin infused rats at baseline and the clamp (n ≥ 6). All error bars are s.e.m.; * P < 0.05, ** P < 0.01, *** P < 0.001 versus vehicle + 1 mU · kg−1 · min−1 clamp group if not otherwise indicated. # P < 0.05 versus vehicle + 3 mU· kg−1 · min−1 clamp group. (See also Fig. S1)
Figure 2
Figure 2. MBH Insulin suppresses hepatic GP, which correlates with lipolytic flux
(A) GIR required to maintain euglycemia. Right, AUC of line graph on the right (n ≥ 6 per group). (B) Baseline hepatic GP (n ≥ 6 per group). (C) Clamp hepatic GP (n ≥ 6 per group). (D) Percent suppression of GP during the clamp from baseline (n ≥ 6 per group). (E) Rate of glucose disposal during the clamp (n ≥ 6 per group). (F) Correlation between Ra glycerol and hepatic GP during the 1mU clamp (n = 11). All error bars are s.e.m.; * P < 0.05, ** P < 0.01, *** P < 0.001 versus vehicle + 1 mU · kg−1 · min−1 clamp group. (See also Fig. S2)
Figure 3
Figure 3. MBH insulin suppresses Hsl activation and increases lipogenic protein expression
(A, B) MBH insulin suppresses lipolysis and induces lipogenesis in WAT. Left, representative Western blot analyses of epidydimal fat pads from clamped animals. Right, quantification of the Western blot analyses (n ≥ 5 per group). (C) Lipid-droplet-depleted cytosolic triglyceride hydrolase activity (n ≥ 8 per group, one-tailed t-test was applied). (D) FAS activity measured in perirenal fat depots (n = 4 per group, one-tailed t-test was applied) Top, quantifications; Bottom, Western blot analyses (n ≥ 3 per group). All error bars are s.e.m.; * P < 0.05 vehicle group. (See also Fig. S3)
Figure 4
Figure 4. Acute inhibition of endogenous MBH insulin signaling is sufficient to unrestrain lipolysis in WAT, which depends on sympathetic innervation
(A) MBH insulin suppresses Hsl activation to a similar degree as surgical denervation or selective pharmacological sympathectomy of the epidydimal fat pad, indicating that insulin suppresses lipolysis through a reduction of sympathetic nervous system outflow to WAT. (B) Validation of the insulin receptor antagonist in vivo. S961 was co–infused with insulin in equimolar amounts into the 3rd ventricle of male SD rats. S961 blocked insulin induced MBH insulin receptor phosphorylation (n = 3 per group) (C) Schematic study outline. Male SD rats were infused with glycerol tracer and received either vehicle S961 for 4 hrs into the MBH. (D) Ra glycerol of MBH vehicle and S961 infused rats as per protocol depicted in Fig. 4C (n ≥ 4 per group) (E) Ra glycerol of sham and pharmacologically sympathectomized rats that were either infused with MBH S961 or vehicle. A similar protocol as depicted in Fig. 5C was used (n ≥ 6 per group). (F) WAT NE levels in sham versus 6–OHDA denervated rats (n = 4 per group). All error bars are s.e.m.; * P < 0.05, ** P < 0.01 versus vehicle group. ### P < 0.001 versus ICV vehicle and ICV insulin + S961 group (See also Fig. S4).
Figure 5
Figure 5. Genetic disruption of neuronal insulin signaling increases whole body lipolytic flux and impairs the switch from fasting to re–feeding
(A) Schematic representation of the clamp studies in NIRKO mice. Following a 16 hr fast, NIRKO and littermate control mice were subjected to a 110 min 4 mU · kg−1 · min−1 hyperinsulinemic euglycemic clamp study. (B) Baseline and clamp glycerol fluxes as assessed by [2H–5]–glycerol tracer infusion are increased in the NIRKO mice (n ≥ 5 per group). (C) Plasma β–hydroxybutyrate levels are elevated in the NIRKO mice following a 16 hr fasting challenge (n = 9 per group). (D) Depiction of the fasting re–feeding protocol (E) Plasma NEFA levels before and after re–feeding. Insert depicts % suppression of plasma NEFA levels after food intake (n ≥ 7 per group) (F) Plasma insulin before and after re feeding (n ≥ 8 per group) (G) Food intake during re-feeding (n ≥ 9 per group) (H) Bodyweights after fasting (n ≥ 9 per group). All error bars are s.e.m.; * P < 0.05 versus control mice. (See also Fig. S5 and Tab. S1)
Figure 6
Figure 6. Loss of neuronal insulin receptor signaling impairs de novo lipogenesis in WAT
(A) Left, representative Western blot analyses of lipogenic protein expression and the activation state of Atpcl in epidydimal fat pads obtained at the end of the clamp study. Right, quantification of Western blot data compared to littermate control mice (n ≥ 5 per group). (B) De novo lipogenesis (DNL) index calculated using the ratio of palmitic (16:0) to linoleic acid (18:2n6) (n ≥ 5 per group). (C) Differences of WAT fatty acid species of overnight fasted NIRKO and control mice. Arrowhead marks palmitoleate. (n = 6 per group) (D) Correlation between the expression of lipogenic proteins and palmitoleate levels (n = 11). All error bars are s.e.m.; * P < 0.05, ** P < 0.01 versus control mice.
Figure 7
Figure 7. Proposed model of the role of brain insulin in regulating WAT metabolism
Insulin inhibits WAT lipolysis through both direct and indirect effects: insulin binding to the insulin receptor expressed on adipocytes results in inactivation of PDE3B leading to the degradation of cAMP (Degerman et al., 1990; Smith et al., 1991). We propose that in addition to the direct effects of insulin on adipocytes, hypothalamic insulin signaling suppresses lipolysis and induces lipogenesis indirectly by dampening SNS outflow to WAT. The reduction in lipolysis contributes to a decrease in hepatic GP by limiting the flux of the gluconeogenic precursor glycerol and NEFAs, which provide energy substrates for gluconeogenesis.
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