Exploring the emerging complexity in transcriptional regulation of energy homeostasis

Key Points

  • In this Review, we try to provide translational researchers with a simplified but accurate understanding of how energy homeostasis is regulated at the transcriptional level. We introduce the many components involved in manipulating transcription and explain how they are involved in the regulation of energy homeostasis.

  • We discuss the key intracellular and extracellular ligand-dependent and cell membrane receptor-dependent transcription factors involved in energy homeostasis and their transcriptional co-regulators.

  • We summarize what are likely to be causal links of transcription factor mutations and human disease.

  • We discuss in brief the new emerging field of intergenerational transcriptional control of metabolism.

  • Crosstalk between multiple signalling cascades and transcription factors and co-regulators, in the form of post-transcriptional modifications, provides the key mode of their integration into the cellular context.

  • With our increasing understanding of how chromatin provides an interface between transcription factors, co-regulators and the DNA blueprint, we have witnessed a dramatic change in our understanding of the complexity of gene regulation. We outline how various metabolites influence the establishment and removal of chromatin marks.

  • We provide insights into how emerging concepts such as non-coding RNAs, genome accessibility and chromosome conformation transform the field of transcriptional control of energy homeostasis.


Obesity and its associated diseases are expected to affect more than 1 billion people by the year 2030. These figures have sparked intensive research into the molecular control of food intake, nutrient distribution, storage and metabolism — processes that are collectively termed energy homeostasis. Recent decades have also seen dramatic developments in our understanding of gene regulation at the signalling, chromatin and post-transcriptional levels. The seemingly exponential growth in this complexity now poses a major challenge for translational researchers in need of simplified but accurate paradigms for clinical use. In this Review, we consider the current understanding of transcriptional control of energy homeostasis, including both transcriptional and epigenetic regulators, and crosstalk between pathways. We also provide insights into emerging developments and challenges in this field.

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Figure 1: Whole-body energy homeostasis.
Figure 2: Transcriptional regulatory networks in positive and negative energy balance.
Figure 3: The interface between metabolism and epigenetic regulation of transcription.


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A.L. and J.A.P. are supported by the Max Planck Society, EU-FP7, DFG and an ERC Starting Grant. J.M.P. is supported by the Austrian Academy of Sciences and an Advanced ERC grant. Owing to the broad scope of this Review, the authors could not cite all the original publications and had to rely heavily on citation of more focused review articles. The authors apologize to all authors not cited who have made important contributions.

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Correspondence to J. Andrew Pospisilik or Josef M. Penninger.

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The endocrine system refers to tissues that secrete hormones directly into the circulatory system to be transported to distant target organs.

Catabolic processes

Processes that break down nutrients to release energy during times of need: for example, during fasting, stress, cold or exercise.


Essential nutrients required in large amounts, such as fat, carbohydrates and proteins.


The oxidative process by which fatty acids are broken down in the mitochondria to generate acetyl-CoA, NADH and FADH2.

Anabolic processes

Biosynthetic and storage processes favoured during energy excess, to store energy for times of need.

Afferent neurons

Neurons that carry nerve impulses from peripheral tissues such as muscles and glands towards the central nervous system. They are also known as sensory neurons.

Efferent neurons

Neurons that carry nerve impulses away from the central nervous system to effector tissues such as muscles and glands. They are also known as motor or effector neurons.


The population of microorganisms that live in and on our body.

Glucagon-like peptide 1

An endocrine hormone secreted by the gut upon feeding, leading to increased insulin secretion in a glucose-dependent manner.

Glucose-dependent insulinotropic polypeptide

A hormone secreted by the gut upon feeding that binds to receptors on β-cells, leading to insulin secretion.


A hunger hormone secreted by the stomach that increases appetite by regulating energy usage.


A peptide hormone formed in the pancreas by β-cells. Insulin signalling leads to increased glucose uptake, and glycogen and lipid synthesis.


A peptide hormone formed in the pancreas by α-cells. Glucagon opposes the action of insulin, leading to glycogen breakdown and lipolysis to generate glucose, which is released into the bloodstream.


Hormones secreted by the liver.

White adipose tissue

A type of adipose tissue that specializes in lipid storage. It is the most important storage tissue and constitutes ideally about 20–25% of the human body. Each white adipocyte usually contains a single large lipid droplet.


Hormones secreted by adipose tissue.


A hormone released by adipocytes, signalling the status of energy stores and regulating appetite by inhibiting hunger.


An adipokine that acts locally and globally to regulate inflammatory pathways, apoptosis and insulin sensitivity.

Basal metabolic rate

The minimum energy required in a time unit at resting state in a temperature- neutral environment in the post-absorptive state.

Brown adipose tissue

A type of adipose tissue that specializes in heat production and is especially abundant in newborns and hybernating animals. Brown adipocytes are characterized by multilobular lipid droplets and a high number of mitochondria.


A derivative or by-product of cholesterol metabolism.


A complex of DNA, proteins and RNAs constituting eukaryotic chromosomes.

Bile acids

Steroid acids produced in the liver from cholesterol. They are secreted into the intestine, where they are important for lipid solubilization and absorption.

Linoleic acid

A polyunsaturated omega-6 fatty acid belonging to the family of essential fatty acids, which cannot be synthesized by the body itself.

Pioneer transcription factors

Transcription factors that bind directly to DNA in the context of condensed (silenced) chromatin, with the ability to alter the chromatin environment, making it more or less accessible to other transcription factors.


Glucagon-producing endocrine cells in the pancreas.


Insulin-producing endocrine cells in the pancreas.

Arcuate nucleus

A group of neurons in the hypothalamus involved in appetite and feeding.


(POMC). A polypeptide hormone precursor that upon cleavage gives rise to several important biologically active peptides, some of which act on distant brain areas involved in feeding behaviour, leading to decreased appetite and increased energy expenditure.


Describes substances that decrease food intake and body weight.

Agouti-related peptide

(AgRP). A neuropeptide that is co-expressed with neuropeptide Y (NPY) and leads to increased appetite and decreased metabolism and energy expenditure.


Describes substances that increase food intake and body weight.

Mammalian target of rapamycin complex 1

A protein complex that functions as a sensor for energy and nutrients, and activates protein synthesis.

Histone code

This hypothesis suggested that distinct histone modifications are specifically recognized by proteins to bring about distinct downstream events.

Hypoxia inducible factor 1α

A transcription factor that is expressed in response to low oxygen concentrations.

AMP-activated protein kinase

(AMPK). An enzyme that plays an essential part in cellular energy homeostasis.

Histone variant

A non-canonical type of histone, with distinct amino acid sequence. Histone variants get incorporated into chromatin only upon eviction of canonical histones.

Unfolded protein response

An endoplasmic reticulum-mediated stress response. It is activated upon accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum, leading to translation attenuation and cell cycle arrest.


The selective degradation of mitochondria by autophagy.


The degradation of unnecessary or non-functional cellular components through a specialized organelle called the lysosome. This provides the cell with energy and building blocks during starvation.

Ketogenic diet

A high-fat, medium-protein, low-carbohydrate diet that forces the body to burn fat rather than carbohydrates.

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Lempradl, A., Pospisilik, J. & Penninger, J. Exploring the emerging complexity in transcriptional regulation of energy homeostasis. Nat Rev Genet 16, 665–681 (2015). https://doi.org/10.1038/nrg3941

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