Impact of Brain Fatty Acid Signaling on Peripheral Insulin Action in Mice

Susanne Neschen; Moya Wu; Christiane Fuchs; Ivan Kondofersky; Fabian J. Theis; Martin Hrabě de Angelis; Hans-Ulrich Häring; Tina Sartorius

doi:10.1055/a-0735-9533

Experimental and Clinical Endocrinology & Diabetes, Inhaltsverzeichnis

Exp Clin Endocrinol Diabetes 2020; 128(01): 20-29
DOI: 10.1055/a-0735-9533

Article

Impact of Brain Fatty Acid Signaling on Peripheral Insulin Action in Mice

Susanne Neschen

¹Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

²German Center for Diabetes Research (DZD), Neuherberg, Germany

,

Moya Wu

¹Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

²German Center for Diabetes Research (DZD), Neuherberg, Germany

,

Christiane Fuchs

³Institute of Computational Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

⁴Center for Mathematics, Chair of Mathematical Modeling of Biological Systems, Technical University of Munich, Garching, Germany

,

Ivan Kondofersky

³Institute of Computational Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

⁴Center for Mathematics, Chair of Mathematical Modeling of Biological Systems, Technical University of Munich, Garching, Germany

,

Fabian J. Theis

³Institute of Computational Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

⁴Center for Mathematics, Chair of Mathematical Modeling of Biological Systems, Technical University of Munich, Garching, Germany

,

Martin Hrabě de Angelis

¹Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

²German Center for Diabetes Research (DZD), Neuherberg, Germany

,

Hans-Ulrich Häring

²German Center for Diabetes Research (DZD), Neuherberg, Germany

⁵Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tuebingen, Tuebingen, Germany

⁶Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen (IDM), Tuebingen, Germany

,

Tina Sartorius

²German Center for Diabetes Research (DZD), Neuherberg, Germany

⁵Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tuebingen, Tuebingen, Germany

⁶Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen (IDM), Tuebingen, Germany

› Institutsangaben

Abstract

Aims and Methods Glucose homeostasis and energy balance are under control by peripheral and brain processes. Especially insulin signaling in the brain seems to impact whole body glucose homeostasis and interacts with fatty acid signaling. In humans circulating saturated fatty acids are negatively associated with brain insulin action while animal studies suggest both positive and negative interactions of fatty acids and insulin brain action. This apparent discrepancy might reflect a difference between acute and chronic fatty acid signaling. To address this question we investigated the acute effect of an intracerebroventricular palmitic acid administration on peripheral glucose homeostasis. We developed and implemented a method for simultaneous monitoring of brain activity and peripheral insulin action in freely moving mice by combining radiotelemetry electrocorticography (ECoG) and euglycemic-hyperinsulinemic clamps. This method allowed gaining insight in the early kinetics of brain fatty acid signaling and its contemporaneous effect on liver function in vivo, which, to our knowledge, has not been assessed so far in mice.

Results Insulin-induced brain activity in the theta and beta band was decreased by acute intracerebroventricular application of palmitic acid. Peripherally it amplified insulin action as demonstrated by a significant inhibition of endogenous glucose production and increased glucose infusion rate. Moreover, our results further revealed that the brain effect of peripheral insulin is modulated by palmitic acid load in the brain.

Conclusion These findings suggest that insulin action is amplified in the periphery and attenuated in the brain by acute palmitic acid application. Thus, our results indicate that acute palmitic acid signaling in the brain may be different from chronic effects.

Key words

brain - electrocorticography - euglycemic-hyperinsulinemic clamps - fatty acids - palmitic acid - radiotelemetry

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References
1 Kleinridders A, Ferris HA, Cai W. et al. Insulin action in brain regulates systemic metabolism and brain function. Diabetes 2014; 63: 2232-2243
2 Vogt MC, Bruning JC. CNS insulin signaling in the control of energy homeostasis and glucose metabolism - from embryo to old age. Trends Endocrinol Metab 2013; 24: 76-84
3 Schwartz MW, Woods SC, Porte Jr. D. et al. Central nervous system control of food intake. Nature 2000; 404: 661-671
4 Tschritter O, Preissl H, Hennige AM. et al. High cerebral insulin sensitivity is associated with loss of body fat during lifestyle intervention. Diabetologia 2012; 55: 175-182
5 Obici S, Zhang BB, Karkanias G. et al. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 2002; 8: 1376-1382
6 Prodi E, Obici S. Minireview: the brain as a molecular target for diabetic therapy. Endocrinology 2006; 147: 2664-2669
7 Heni M, Kullmann S, Preissl H. et al. Impaired insulin action in the human brain: causes and metabolic consequences. Nat Rev Endocrinol 2015; 11: 701-711
8 Tschritter O, Preissl H, Hennige AM. et al. The cerebrocortical response to hyperinsulinemia is reduced in overweight humans: a magnetoencephalographic study. Proc Natl Acad Sci USA 2006; 103: 12103-12108
9 Tschritter O, Preissl H, Yokoyama Y. et al. Variation in the FTO gene locus is associated with cerebrocortical insulin resistance in humans. Diabetologia 2007; 50: 2602-2603
10 Tschritter O, Preissl H, Hennige AM. et al. The insulin effect on cerebrocortical theta activity is associated with serum concentrations of saturated nonesterified Fatty acids. J Clin Endocrinol Metab 2009; 94: 4600-4607
11 Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997; 46: 3-10
12 Hennige AM, Sartorius T, Lutz SZ. et al. Insulin-mediated cortical activity in the slow frequency range is diminished in obese mice and promotes physical inactivity. Diabetologia 2009; 52: 2416-2424
13 Sartorius T, Lutz SZ, Hoene M. et al. Toll-like receptors 2 and 4 impair insulin-mediated brain activity by interleukin-6 and osteopontin and alter sleep architecture. FASEB J 2012; 26: 1799-1809
14 Veerkamp JH, Zimmerman AW. Fatty acid-binding proteins of nervous tissue. J Mol Neurosci 2001; 16: 133-142
15 Lam TK, Pocai A, Gutierrez-Juarez R. et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med 2005; 11: 320-327
16 Obici S, Feng Z, Morgan K. et al. Central administration of oleic acid inhibits glucose production and food intake. Diabetes 2002; 51: 271-275
17 Pocai A, Lam TK, Gutierrez-Juarez R. et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature 2005; 434: 1026-1031
18 Clore JN, Stillman JS, Li J. et al. Differential effect of saturated and polyunsaturated fatty acids on hepatic glucose metabolism in humans. Am J Physiol Endocrinol Metab 2004; 287: E358-E365
19 Xiao C, Giacca A, Carpentier A. et al. Differential effects of monounsaturated, polyunsaturated and saturated fat ingestion on glucose-stimulated insulin secretion, sensitivity and clearance in overweight and obese, non-diabetic humans. Diabetologia 2006; 49: 1371-1379
20 Sartorius T, Ketterer C, Kullmann S. et al. Monounsaturated fatty acids prevent the aversive effects of obesity on locomotion, brain activity, and sleep behavior. Diabetes 2012; 61: 1669-1679
21 Boden G, Chen X, Ruiz J. et al. Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 1994; 93: 2438-2446
22 Lam TK, Carpentier A, Lewis GF. et al. Mechanisms of the free fatty acid-induced increase in hepatic glucose production. Am J Physiol Endocrinol Metab 2003; 284: E863-E873
23 Lewis GF, Vranic M, Harley P. et al. Fatty acids mediate the acute extrahepatic effects of insulin on hepatic glucose production in humans. Diabetes 1997; 46: 1111-1119
24 Rebrin K, Steil GM, Mittelman SD. et al. Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs. J Clin Invest 1996; 98: 741-749
25 Wang PY, Caspi L, Lam CK. et al. Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature 2008; 452: 1012-1016
26 Caspi L, Wang PY, Lam TK. A balance of lipid-sensing mechanisms in the brain and liver. Cell Metab 2007; 6: 99-104
27 Kim JK, Fillmore JJ, Chen Y. et al. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci USA 2001; 98: 7522-7527
28 Pocai A, Obici S, Schwartz GJ. et al. A brain-liver circuit regulates glucose homeostasis. Cell Metab 2005; 1: 53-61
29 Ross RA, Rossetti L, Lam TK. et al. Differential effects of hypothalamic long-chain fatty acid infusions on suppression of hepatic glucose production. Am J Physiol Endocrinol Metab 2010; 299: E633-E639
30 Thaler JP, Yi CX, Schur EA. et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 2012; 122: 153-162
31 Crainiceanu CM, Staicu AM, Ray S. et al. Bootstrap-based inference on the difference in the means of two correlated functional processes. Stat Med 2012; 31: 3223-3240
32 Kaufmann S, Fuchs C, Gonik M. et al. Inter-chromosomal contact networks provide insights into Mammalian chromatin organization. PLoS One 2015; 10: e0126125
33 Holland WL, Bikman BT, Wang LP. et al. Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest 2011; 121: 1858-1870
34 Summers SA. Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res 2006; 45: 42-72
35 Boden G, She P, Mozzoli M. et al. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver. Diabetes 2005; 54: 3458-3465
36 Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest 2000; 106: 171-176
37 Lam TK, Yoshii H, Haber CA. et al. Free fatty acid-induced hepatic insulin resistance: a potential role for protein kinase C-delta. Am J Physiol Endocrinol Metab 2002; 283: E682-E691
38 Spanswick D, Smith MA, Mirshamsi S. et al. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci 2000; 3: 757-758
39 Konner AC, Janoschek R, Plum L. et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab 2007; 5: 438-449
40 Banks WA, Jaspan JB, Huang W. et al. Transport of insulin across the blood-brain barrier: saturability at euglycemic doses of insulin. Peptides 1997; 18: 1423-1429
41 Woods SC, Seeley RJ, Baskin DG. et al. Insulin and the blood-brain barrier. Curr Pharm Des 2003; 9: 795-800
42 Morton GJ, Cummings DE, Baskin DG. et al. Central nervous system control of food intake and body weight. Nature 2006; 443: 289-295
43 Lam CK, Chari M, Rutter GA. et al. Hypothalamic nutrient sensing activates a forebrain-hindbrain neuronal circuit to regulate glucose production in vivo. Diabetes 2011; 60: 107-113

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